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Inflammatory pain is caused by damaged tissue or noxious stimuli, accompanied by the release of inflammatory mediators that often leads to severe hyperalgesia and allodynia with limited therapy options. Recently, a novel mitochondrial-derived peptide (named MOTS-c) was reported to regulate obesity, metabolic homeostasis and inflammatory response. The aim of this study was to investigate the effects of MOTS-c and its related regulatory mechanisms involved in inflammatory pain. Male Kunming mice (8–10 weeks-old) were intraplantar injected with formalin, capsaicin, λ-Carrageenan and complete Freund adjuvant (CFA) to establish acute and chronic inflammatory pain. The effects of MOTS-c on the above inflammatory pain mice and its underlying mechanisms were examined by behavioral tests, quantitative polymerase chain reaction (qPCR), western blotting, enzyme linked immunosorbent assay (ELISA), immunohistochemistry (IHC) and immunofluorescence (IF). Behavioral experiments investigated the potential beneficial effects of MOTS-c on multiple acute and chronic inflammatory pain in mice. The results showed that MOTS-c treatment produced potent anti-allodynic effects in formalin-induced acute inflammatory pain, capsaicin-induced nocifensive behaviors and λ-Carrageenan/CFA-induced chronic inflammatory pain model. Further mechanistic studies revealed that central MOTS-c treatment significantly ameliorated CFA-evoked the release of inflammatory factors and activation of glial cells and neurons in the spinal dorsal horn. Moreover, peripheral MOTS-c treatment reduced CFA-evoked inflammatory responses in the surface structure of hindpaw skin, accompanied by inhibiting excitation of peripheral calcitonin gene-related peptide (CGRP) and P2X3 nociceptive neurons. The present study indicates that MOTS-c may serve as a promising therapeutic target for inflammatory pain. [ABSTRACT FROM AUTHOR]

The incidence of heatstroke (HS) is not particularly high; however, once it occurs, the consequences are serious. It is reported that calcitonin gene-related peptide (CGRP) is protective against brain injury in HS rats, but detailed molecular mechanisms need to be further investigated. In this study, we further explored whether CGRP inhibited neuronal apoptosis in HS rats via protein kinase A (PKA)/p-cAMP response element-binding protein (p-CREB) pathway. We established a HS rat model in a pre-warmed artificial climate chamber with a temperature of (35.5 ± 0.5) °C and a relative humidity of 60% ± 5%. Heatstress was stopped once core body temperature reaches above 41 °C. A total of 25 rats were randomly divided into 5 groups with 5 animals each: control group, HS group, HS+CGRP group, HS+CGRP antagonist (CGRP8-37) group, and HS+CGRP+PKA/p-CREB pathway blocker (H89) group. A bolus injection of CGRP was administered to each rat in HS+CGRP group, CGRP8-37 (antagonist of CGRP) in HS+CGRP8-37 group, and CGRP with H89 in HS+CGRP+H89 group. Electroencephalograms were recorded and the serum concentration of S100B, neuron-specific enolase (NSE), neuron apoptosis, activated caspase-3 and CGRP expression, as well as pathological morphology of brain tissue were detected at 2 h, 6 h, and 24 h after HS in vivo. The expression of PKA, p-CREB, and Bcl-2 in rat neurons were also detected at 2 h after HS in vitro. Exogenous CGRP, CGRP8-37, or H89 were used to determine whether CGRP plays a protective role in brain injury via PKA/p-CREB pathway. The unpaired t -test was used between the 2 samples, and the mean ± SD was used for multiple samples. Double-tailed p < 0.05 was considered statistically significant. Electroencephalogram showed significant alteration of θ (54.50 ± 11.51 vs. 31.30 ± 8.71, F = 6.790, p = 0.005) and α wave (16.60 ± 3.21 vs. 35.40 ± 11.28, F = 4.549, p = 0.020) in HS group compared to the control group 2 h after HS. The results of triphosphate gap terminal labeling (TUNEL) showed that the neuronal apoptosis of HS rats was increased in the cortex (9.67 ± 3.16 vs. 1.80 ± 1.10, F = 11.002, p = 0.001) and hippocampus (15.73 ± 8.92 vs. 2.00 ± 1.00, F = 4.089, p = 0.028), the expression of activated caspase-3 was increased in the cortex (61.76 ± 25.13 vs. 19.57 ± 17.88, F = 5.695, p = 0.009) and hippocampus (58.60 ± 23.30 vs. 17.80 ± 17.62, F = 4.628, p = 0.019); meanwhile the expression of serum NSE (5.77 ± 1.78 vs. 2.35 ± 0.56, F = 5.174, p = 0.013) and S100B (2.86 ± 0.69 vs. 1.35 ± 0.34, F = 10.982, p = 0.001) were increased significantly under HS. Exogenous CGRP decreased the concentrations of NSE and S100B, and activated the expression of caspase-3 (0.41 ± 0.09 vs. 0.23 ± 0.04, F = 32.387, p < 0.001) under HS; while CGRP8-37 increased NSE (3.99 ± 0.47 vs. 2.40 ± 0.50, F = 11.991, p = 0.000) and S100B (2.19 ± 0.43 vs. 1.42 ± 0.30, F = 4.078, p = 0.025), and activated the expression caspase-3 (0.79 ± 0.10 vs. 0.23 ± 0.04, F = 32.387, p < 0.001). For the cell experiment, CGRP increased Bcl-2 (2.01 ± 0.73 vs. 2.15 ± 0.74, F = 8.993, p < 0.001), PKA (0.88 ± 0.08 vs. 0.37 ± 0.14, F = 20.370, p < 0.001), and p-CREB (0.87 ± 0.13 vs. 0.29 ± 0.10, F = 16.759, p < 0.001) levels; while H89, a blocker of the PKA/p-CREB pathway reversed the expression. CGRP can protect against HS-induced neuron apoptosis via PKA/p-CREB pathway and reduce activation of caspase-3 by regulating Bcl-2. Thus CGRP may be a new target for the treatment of brain injury in HS. [ABSTRACT FROM AUTHOR]

Copyright of Actualités Pharmaceutiques is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Pulp calcification (PC) often appears in strong association with nerve fiber bundles, which indicates the important role of dental nerves in the formation of PC. Additionally, given that sensory nerves and calcitonin gene-related peptide (CGRP) secreted from sensory nerve fibers are involved in physiological and pathological bone formation, we aimed to determine whether chronic irritation of sensory nerves can promote the occurrence of PC. A sensory nerve irritation rat model was established via ligation of the inferior alveolar nerve (IAN), and face grooming behavior was analyzed as a measure of pain sensation. Two months post-surgery, PC was determined by imaging and histologic analyses. Rats in the IAN-chronic constriction injury (IAN-CCI) group showed spontaneous pain-associated behavior after the operations and pain tolerance on the 60th postoperative day. The imaging and histological analysis showed more calcified particles in the IAN-innervated first and second molars after day 60 of the dental sensory nerve irritation. These calcified masses had a dentin-like structure that contained sparse, irregularly oriented tubules. Compared to the control and sham groups, the odontoblasts located in the periphery of radicular pulp aligned along a thicker layer of predentin; which expressed more nestin with longer and stouter processes in the IAN-CCI group. Additionally, more CGRP-positive nerves were observed in the IAN-CCI group. Irritation of sensory nerves promotes PC formation, and the increased density of CGRP-immunolabeled fibers probably contributes to this process. This highlights the significance of dental sensory nerves in the formation of PC. [ABSTRACT FROM AUTHOR]

What textbooks usually call the sublingual gland in humans is in reality a tissue mass of two types of salivary glands, the anteriorly located consisting of a cluster of minor sublingual glands and the posteriorly located major sublingual gland with its outlet via Bartholin's duct. Only recently, the adrenergic and cholinergic innervations of the major sublingual gland was reported, while information regarding the neuropeptidergic and nitrergic innervations is still lacking. Bioptic and autoptic specimens of the human major sublingual gland were examined by means of immunohistochemistry for the presence of vasoactive intestinal peptide (VIP)-, neuropeptide Y (NPY)-, substance P (SP)-, calcitonin gene related-peptide (CGRP)-, and neuronal nitric oxide synthase (nNOS)-labeled neuronal structures. As to the neuropeptidergic innervation of secretory cells (here in the form of mucous tubular and seromucous cells), the findings showed many VIP-containing nerves, few NPY- and SP-containing nerves and a lack of CGRP-labeled nerves. As to the neuropeptidergic innervation of vessels, the number of VIP-containing nerves was modest, while, of the other neuropeptide-containing nerves under study, only few (SP and CGRP) to very few (NPY) nerves were observed. As to the nitrergic innervation, nNOS-containing nerves were very few close to secretory cells and even absent around vessels. The various innervation patterns may suggest potential transmission mechanisms involved in secretory and vascular responses of the major sublingual gland. • Neuropeptidergic nerves are mostly around acini. • Neuropeptidergic innervation of vessels is modest to rare. • Vasoactive intestinal peptide is the dominating neuropeptide. • Nitrergic innervation is poor. • Non-adrenergic, non-cholinergic innervations may regulate secretory and vascular functions. [ABSTRACT FROM AUTHOR]

Migraine is a highly disabling and prevalent neurological disorder. A peptide, calcitonin gene-related peptide, was identified as involved in migraine pathophysiology and monoclonal anti-CGRP antibodies have been developed. To describe the clinical characteristics and therapeutic response of migraine patients treated with monoclonal antibodies. An observational, prospective, uncontrolled, and descriptive study was carried out with a sample of 112 consecutive patients with episodic or chronic migraine treated with monoclonal antibodies. Eight patients did not return for the following medical consultation. They were excluded from the study. A total of 104 patients were described. There was a predominance of episodic migraine. Before treatment, the average frequency of headache was 15.3 ± 8.5 days per month, during the previous three months. Monoclonal antibodies were prescribed at the following frequency: erenumab (49%), galcanezumab (45.2%), and fremanezumab (5.8%). After the third month, the reduction in headache attacks was greater than 50% in 57.7% of patients. Adverse events were referred by 18.3% of patients, in this order of frequency: constipation (7.7%), insomnia (2.9%), vertigo (1.9%), erythema at the injection site (1.9%), arthralgia (1%), nasopharyngitis (1%), facial and hand edema (1%), irritation at the injection site (1%), and paresthesia at the injection site (1%). This described analysis of migraine patients who used monoclonal antibodies presented one of the first Brazilian experiences with real-world patients. Our results may enlighten clinicians on the outcomes and ways of prescribing anti-CGRP antibodies. [ABSTRACT FROM AUTHOR]

Managing chronic pain remains a major unmet clinical challenge. Patients can be treated with a range of interventions, but pharmacotherapy is the most common. These include opioids, antidepressants, calcium channel modulators, sodium channel blockers, and nonsteroidal anti-inflammatory drugs. Many of these drugs target a particular mechanism; however, chronic pain in many diseases is multifactorial and induces plasticity throughout the sensory neuroaxis. Furthermore, comorbidities such as depression, anxiety, and sleep disturbances worsen quality of life. Given the complexity of mechanisms and symptoms in patients, it is unsurprising that many fail to achieve adequate pain relief from a single agent. The efforts to develop novel drug classes with better efficacy have not always proved successful; a multimodal or combination approach to analgesia is an important strategy in pain control. Many patients frequently take more than one medication, but high-quality evidence to support various combinations is often sparse. Ideally, combining drugs would produce synergistic action to maximize analgesia and reduce side effects, although sub-additive and additive analgesia is still advantageous if additive side-effects can be avoided. In this review, we discuss pain mechanisms, drug actions, and the rationale for mechanism-led treatment selection. Abbreviations: COX – cyclooxygenase, CGRP – calcitonin gene-related peptide, CPM – conditioned pain modulation, NGF – nerve growth factor, NNT – number needed to treat, NMDA – N-methyl-d-aspartate, NSAID – nonsteroidal anti-inflammatory drugs, TCA – tricyclic antidepressant, SNRI – serotonin-noradrenaline reuptake inhibitor, QST – quantitative sensory testing. [ABSTRACT FROM AUTHOR]

Objective: The purpose of the current study was to evaluate the modulation of Calcitonin gene-related peptide (CGRP) associated to the efficacy of Electroacupuncture (EA) in the reduction of climacteric symptoms.Methods: Nine women between 51 and 59 years old with climacteric syndrome in menopause or perimenopause were included. Patients with hormone replacement therapy, psychiatric treatment with antidepressants, or acupuncture treatment in the last 3 months were excluded. A 4 Hz EA treatment was performed at acupoints Shenshu (BL-23), Pishu (BL-20), Guanyuan (REN-4), Taixi (KID-3), Fuliu (KID-7), Sanyinjiao (SP-6) and Neiguan (P-6) points. Women were treated two times a week for five consecutive weeks for a total treatment of 10 sessions. The menopause rating scale (MRS) was used to evaluate symptoms reduction and CGRP gene expression was measured before and after 10 EA session.Results: The results shown that climacteric symptoms diminish significantly after EA therapy. CGRP gene expression was down-regulated, evidencing a decrease of 5-fold after EA therapy respect to the initial condition.Conclusion: EA treatment was associated with improvement in patients with climacteric syndrome and may be related to modulation of CGRP levels. [ABSTRACT FROM AUTHOR]

Objective: To systematically review the literature to identify controlled clinical trials evaluating the effectiveness of deep dry needling (DDN) in the treatment of patients with chronic masticatory myofascial pain (MMP).Methods: The sample size for a clinical trial was calculated and involved five patients who consecutively presented for treatment of MMP. The percentage of change in the means of three consecutive measurements of the pressure pain threshold (PPT) of myofascial trigger points (MTPs) was calculated and the statistical significance of this difference evaluated using the Wilcoxon test.Results: Twenty-five studies were considered for inclusion based on title and abstract. Only 2 studies met the inclusion criteria and were used to calculate the sample size. DDN significantly increased (p = 0.04) the PPT in MTP (44.6%) compared with sham procedure (-5.5%).Conclusion: Patients with chronic MMP treated with DDN of MTPs showed an increase in PPT measurements on the experimental side.Abbreviations: CGRP: calcitonin gene-related peptide; DC/TMD: diagnostic criteria for temporomandibular disorders; DDN: deep dry needling; DN: dry needling; LILACS: Latin American and Caribbean Health Sciences; MMP: masticatory myofascial pain; MTP: myofascial trigger point; MTPs: myofascial trigger points; PPT: pressure pain threshold; RCTs: randomized clinical trials; SciELO: Scientific Electronic Library Online; SP: Substance P; TMD: temporomandibular disorders. [ABSTRACT FROM AUTHOR]

Introduction: Sensory nerves of the tooth pulp have been evolved in both deciduous and permanent teeth for conducting possible damages to the teeth. Although it has been reported that the deciduous tooth's pulp is histologically similar to permanent teeth, the difference in the density of nerves between the first and second deciduous molars has been reported in no studies. Aim: The aim of the study was to investigate the histological assay of pulpal nerves and assess the relationship between diameter and density of nerve fibres in the first and second deciduous molar teeth. Materials and methods: In this in vitro study, 15 deciduous first and 16 deciduous second extracted from molar teeth belonging to children aged from 5 to 8 years were studied. After fixation, the decalcified teeth were sectioned and then stained with silver solution and calcitonin gene-related peptide (CGRP) antibody. The mean diameter of myelinated fibres, un-myelinated fibres, and density of peripheral network fibres of dental pulp were examined. Results: The results showed that the mean diameter of myelinated and non-myelinated fibres and density of nerve fibres were significantly more in the second molars (4.269, 2.328 µm, 2.6 fibres per unit area) compared to the first molar teeth (3.793, 2.093 µm, 1.8 fibres per unit area) (P < 0.032, 0.019, 0.003, respectively). An important finding in this study, which is reported for the first time, is the presence of fatty cells (adipocytes) in pulp tissue of some of the first deciduous molars as well as the second molars. Conclusions: Based on the results of the current study, differences between nerve fibres of first and second molar teeth are significant. It could be concluded that the less sensitivity to pain of the first deciduous molars compared with the second deciduous molars, is due to the lower nerve density of this tooth. [ABSTRACT FROM AUTHOR]

This study investigated the effects of wheel-running using the upper limbs following immobilization after inducing arthritis in the knees of rats. Forty male Wistar rats (aged 8 weeks) divided into four groups randomly: arthritis (AR), immobilization after arthritis (Im), wheel-running exercise with the upper limbs following immobilization after arthritis induction (Im+Ex) and sham arthritis induction (Con). The knee joints of the Im and Im+Ex groups were immobilized with a cast for 4 weeks. In the Im+Ex group, wheel-running exercise was administered for 60 min/day (5 times/week). The swelling and the pressure pain threshold (PPT) of the knee joint were evaluated for observing the condition of inflammatory symptoms in affected area, and the paw withdraw response (PWR) was evaluated for observing the condition of secondary hyperalgesia in distant area. Especially, in order to evaluate histological inflammation in the knee joint, the number of macrophage (CD68-positive cells) in the synovium was examined. The expression of calcitonin gene-related peptide (CGRP) in the spinal dorsal horn (L2-3 and L4-5) was examined to evaluate central sensitization. The Im+Ex group showed a significantly better recovery than the Im group in the swelling, PPTs, and PWRs. Additionally, CGRP expression of the spinal dorsal horn (L2-3 and L4-5) in the Im+Ex group was significantly decreased compared with the Im group. According to the results, upper limb exercise can decrease pain in the affected area, reduce hyperalgesia in distant areas, and suppress the central sensitization in the spinal dorsal horn by triggering exerciseinduced hypoalgesia (EIH). [ABSTRACT FROM AUTHOR]

Migraine is a debilitating neurological condition, with a global prevalence rate of 10.68% in men and 18.79% in women. Elucidation of the molecular mechanisms underlying migraines is of great importance for improving the quality of life of patients. The release of the neuropeptide calcitonin gene‐related peptide (CGRP) from trigeminal nerve terminals is involved in the pathogenesis of migraine. Recent studies have shown that up‐regulation of miR‐34a‐5p expression is associated with acute migraine attacks. Here, we investigated whether alteration of the expression of miR‐34a‐5p induces the release of the vasoactive peptide CGRP. We isolated primary rat trigeminal ganglion neurons and performed gain‐ and loss‐of‐function assays to alter the expression level of miR‐34a‐5p. Down‐regulation of miR‐34a‐5p inhibited the expression of interleukin‐1β (IL‐1β)/cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2), decreased IL‐1β, PGE2 and CGRP release, and up‐regulated the expression of silencing information regulator 1 (SIRT1) in trigeminal ganglion, whereas overexpression of miR‐34a‐5p enhanced the expression of IL‐1β/COX2/PGE2, increased the release of IL‐1β, PGE2 and CGRP, and decreased the expression of SIRT1 in trigeminal ganglion. In addition, overexpression of miR‐34a‐5p induced apoptosis in primary rat trigeminal neurons. In summary, these findings suggest that miR‐34a‐5p up‐regulates the IL‐1β/COX2/PGE2 inflammation pathway, induces apoptosis and enhances release of CGRP via inhibition of SIRT1 expression in trigeminal ganglion neurons; thus, miR‐34a‐5p may have potential as a therapeutic target for the treatment of migraine. [ABSTRACT FROM AUTHOR]

To investigate the therapeutic effects of sumatriptan in a rat model of spinal cord injury (SCI) and possible anti-inflammatory and analgesic mechanisms underlying this effect. Using an aneurysm mini-clip model of contusive SCI, T9-10 laminectomies were performed for 60 male rats. Animals were divided into six experimental groups (n = 10 per group) as follows: a minocycline administered positive control group, a saline-vehicle negative control group, a sham-operated group, and three experimental groups which received separate doses of sumatriptan (0.1, 0.3 and 1 mg/kg). Behavioural assessments were used to evaluate locomotor activity and neuropathic pain for 28 days. At the end of the study, spinal cord tissues were collected from sacrificed animals for histopathological analysis. Levels of calcitonin gene-related peptide (CGRP) and two pro-inflammatory cytokines (tumor necrosis factor [TNF]-α and interleukin [IL]-1β) were assessed by the enzyme-linked immunosorbent assay (ELISA). Sumatriptan significantly (P < 0.001) improved the locomotor activity in SCI group. Sumatriptan was also more effective than the positive control, i.e. minocycline (0.3 mg/kg). Additionally, sumatriptan and minocycline similarly attenuated the mechanical and thermal allodynia in SCI (P < 0.001). TNF-α, IL-1β and CGRP levels in sumatriptan- and minocycline-treated groups significantly (P < 0.001) decreased compared to controls. Histopathological analysis also revealed a markedly improvement in hemorrhage followed by inflammatory cell invasion, neuronal vacuolation, and cyst formation in both sumatriptan- and minocycline-treated groups compared to control animals. Sumatriptan improves functional recovery from SCI through its anti-inflammatory effects and reducing pro-inflammatory and pain mediators. [ABSTRACT FROM AUTHOR]

There is conflicting evidence on the effect of physical exercise on migraine development. Present study investigated the impact of treadmill exercise on migraine – associated symptoms and changes in calcitonin gene-related peptide (CGRP) expression in rats with and without maternal deprivation stress (MD). Two days after birth, the male Wistar pups were randomly divided into four groups (n = 6) as follows: intact, exercise, MD, and MD plus exercise. The animals in the MD groups were separated from their dams 4 h per day for 2 weeks. At 8 weeks of age, the rats were exercised on a motor-driven treadmill for 4 weeks. Then, nitroglycerin (NTG) (5 mg/kg/IP) was used to induce migraine and pain-related symptoms were recorded for 90 min. NTG-related thermal hyperalgesia was measured by tail flick and hot plate methods. Finally, immunofluorescence staining of CGRP in trigeminal subnucleus caudalis (Vc) was performed. NTG – produced a significant headache symptoms and thermal hypersensitivity, which were aggravated following physical exercise in stressed or unstressed groups. Besides, NTG administration increased CGRP expression in the Vc of rats. Such effect was overpowered by treadmill running only in rats exposed to MD stress. These findings highlight the worsening effects of treadmill exercise for migraine in rats with and without MD stress. However, inflammatory response can further exacerbate in stressed rats. [ABSTRACT FROM AUTHOR]

Migraine is a common and disabling disorder with substantial personal, social, and economic burden that affects 37 million people in the United States. Risk factors for migraine include age, sex, and genetics. The goal of acute treatment of migraine attacks is to stop the pain and associated symptoms of the migraine attack and return the patient to normal function. The acute treatment landscape for migraine has recently expanded beyond the standard nonsteroidal anti-inflammatory drugs, analgesics, triptans, ergotamines, and combination therapies, to include neuromodulation devices, and recently approved calcitonin gene-related peptide receptor antagonists and a serotonin (5-HT1F) receptor agonist. Unmet acute treatment needs still exist due to lack of efficacy, unwanted side effects, or contraindication to treatment. Effective treatment of migraine requires the clinician to assess the patient, make an accurate diagnosis, and then offer appropriate therapy based on the patient's medical history, comorbidities, and preferences, as well as published clinical evidence. The objective of this narrative review is to familiarize primary care clinicians with the variety of acute treatment options available in the United States today based on clinical trial findings, meta-analyses, evidence-based guidelines, and professional society consensus statements. [ABSTRACT FROM AUTHOR]

Periodontitis is an inflammatory disease caused by bacteria that forms a dental biofilm. Calcitonin gene-related peptide (CGRP) is an anti-inflammatory agent that inhibits osteoclast activity. This study compared the CGRP levels in the gingival crevicular fluid (GCF) from adult and elderly periodontitis patients. Clinical samples were obtained from the GCF of 70 subjects with periodontal diseases, including male and female subjects 60-75 years old (n = 42) and control group adult patients 25-55 years old (n = 28). Measurements of clinical parameters, including the probing pocket depth (PPD) and bleeding on probing, were assessed as diagnostic criteria. A pocket depth was defined as being present if the PPD was ≥3 mm. An enzyme-linked immunosorbent assay was performed to measure the CGRP levels. The level of CGRP in the GCF was slightly higher in adult patients (39.91 pg/μg) than in elderly patients (25.52 pg/μg); however, this result was not statistically significant (p >.05). The level of CGRP in the GCF of periodontitis patients was not dependent on age and was lower in elderly patients. [ABSTRACT FROM AUTHOR]

This study aimed to examine the process of reinnervation during coronal pulp tissue regeneration in a rat model in which rat bone marrow mesenchymal stem cells were implanted in pulpotomized molars. The maxillary first molars of Wistar rats were pulpotomized, and preformed biodegradable porous poly L-lactic acid scaffolds and hydrogel carrying rat bone marrow mesenchymal stem cells were implanted in the pulp chamber. After 3, 7, and 14 days, the implanted teeth were processed for histologic analysis; immunoperoxidase staining for protein gene product 9.5 (a general neuronal marker), calcitonin gene-related peptide (CGRP), or substance P (SP); and real-time polymerase chain reaction for nerve growth factor (NGF) and growth-associated protein 43 (GAP-43) messenger RNA (mRNA) expression. Histologic analysis of the implanted region revealed sparse cellular distribution at 3 days, pulplike tissue with a thin dentin bridge–like structure at 7 days, and dentin bridge–like mineralized tissue formation and resorption of most scaffolds at 14 days. Protein gene product 9.5 and CGRP-immunoreactive nerve fibers showed the lowest density at 3 days and significantly increased until 14 days when the CGRP-immunoreactive fibers reached normal levels. SP-immunoreactive nerve fibers showed the highest density at 7 days and decreased to normal levels at 14 days. NGF mRNA increased with time, whereas GAP-43 mRNA levels peaked at 3 days and subsequently dropped until 14 days. Regeneration/remodeling of SP-immunoreactive and CGRP-immunoreactive nerve fibers with increased mRNA expression of NGF and GAP-43 occurred in a rat model of coronal pulp tissue engineering with bone marrow mesenchymal stem cells. [ABSTRACT FROM AUTHOR]

Pulpitis is an inflammation of dental pulp caused by bacterial proliferation near or within pulpal tissues. In advanced stages, when the inflammation is associated with pulp necrosis, pulp preservation is dependent on dental pulp stem cells (DPSCs) that can differentiate into odontoblastlike cells and produce reparative dentin. In this study, we evaluated the influence of sensory neurons through calcitonin gene-related peptide (CGRP) on DPSC viability and proliferation and the ability of DPSCs to differentiate into mineralizing cells. Commercially available DPSCs were treated with varying doses of CGRP, and metabolic activity, viability, proliferation, and cell death were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays, trypan blue staining, 5-bromo-2'-deoxyuridine cell proliferation assay, and caspase-3 staining, respectively. DPSC differentiation was assessed with alizarin red staining and by quantifying messenger RNA expression of odontoblast makers. CGRP induced a dose-dependent decrease of DPSC metabolic activity that was prevented by the CGRP receptor antagonist CGRP 8-37. The decrease in the proportion of live cells induced by CGRP is associated with a decrease of cell proliferation but not with caspase-3–dependent apoptosis. Interestingly, dexamethasone-induced DPSC differentiation into mineralizing cells was neither inhibited nor enhanced by CGRP treatment. The neuropeptide CGRP has an inhibitory effect on DPSC proliferation but does not enhance or inhibit the differentiation of DPSCs into mineralizing cells. This suggests that CGRP might negatively influence the ability of DPSCs to contribute to regenerative or tissue repair processes. [ABSTRACT FROM AUTHOR]

Trigeminal neuralgia is one of the most common of the neuropathic pains, and it can seriously influence patients' quality of life. Calcitonin gene-related peptide (CGRP) is a type of nociceptive neurotransmitter that is expressed in neurons of the trigeminal ganglion and plays a major part in transmitting pain. The rat model of trigeminal neuralgia was established by causing a chronic constriction injury of the infraorbital nerve (CCI-ION). Male Sprague-Dawley rats (n = 24) were randomly divided into a sham control group (sham, n = 6), sham-treated with palmatine group (sham + palmatine, n = 6), trigeminal nerve model group (TN, n = 6), and trigeminal nerve treated with palmatine group (TN + palmatine, n = 6). Fifteen days after the operation the mechanical response threshold was decreased in the TN group compared with the sham group. From postoperative day 7 to day 15, the mechanical response threshold in the TN + palmatine group significantly increased compared with the TN group. On postoperative day 15 the results of quantitative polymerase chain reaction (qPCR), immunohistochemical staining, and western blotting showed an obvious increase in expression of CGRP and its receptors, serum concentrations of interleukin-1β (IL-1β), and tumour necrosis factor-α (TNF-α), and phosphorylation of protein kinase C (PKC) in the trigeminal ganglia of the TN group compared with the sham group, but these increases could be down-regulated by treatment with palmatine. Palmatine might therefore have therapeutic potential for the treatment of trigeminal neuralgia by inhibiting the expression of CGRP and its receptors in trigeminal ganglia, suppressing the serum concentrations of IL-1β and TNF-α, and decreasing the phosphorylation of PKC in the trigeminal ganglia of affected rats. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the microstructure of blood vessels and nerve fibers between different acupoints in the rat skin from the perspective of histology. The skin tissue at "Qūzé" (曲泽 PC3)" "Dàlíng (大陵 PC7)" and "Zhōngchōng (中冲 PC9)" regions was taken from the rat forelimb along the pericardium meridian, and cut sagittally with a freezing microtome. After that, the skin sections were stained by fluorescent histochemistry and immunohistochemistry with phalloidin and calcitonin gene-related peptide (CGRP) to reveal the microstructure of blood vessels and nerve fibers respectively, and then examined under a laser scanning confocal microscope. The microstructure of blood vessels and nerve fibers was clearly labeled with phalloidin and CGRP, respectively. The blood vessels and nerve fibers were observed in the dermis of "PC3" "PC7" and "PC9" regions, where the bundle of nerve fibers distribute in parallel to the blood vessels, and sent out thin branches to surround the wall of the blood vessels. In contrast, the density of blood vessels and nerve fibers in "PC3" "PC7" and "PC9" were presented orderly in an increased tendency. The results of present study demonstrate the differences of the neurovascular microstructure among "PC3" "PC7" and "PC9" in the rat, providing a histological view to insight into the specificity of different acupoints. [ABSTRACT FROM AUTHOR]

Copyright of Deutsche Zeitschrift für Akupunktur is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Recently, a relationship was found between periodontitis and chronic migraine. Calcitonin gene-related peptide (CGRP) is a key element in migraine pathophysiology. However, no information exists of the potential association between periodontal inflammation and CGRP in chronic migraine. The aim of the study was, therefore, to investigate whether there is a link between periodontitis and peripheral levels of CGRP in a cohort of patients with chronic migraine.Methods: We included 102 chronic migraineurs and 77 age- and sex-matched individuals free of headache/migraine. Full-mouth periodontal parameters were recorded and the periodontal inflamed surface area (PISA) was calculated to quantify the periodontal inflammatory status for each participant. Sociodemographic data and comorbidities were assessed by means of a standard questionnaire. We collected blood samples and serum concentrations were done for CGRP, interleukin (IL)-6 and IL-10.Results: In the chronic migraine group, patients with periodontitis had greater levels of serum CGRP (19.7 ± 6.5 versus 15.3 ± 6.2 pg/mL, P < 0.0001) and IL-6 (15.1 ± 9.2 versus 9.6 ± 6.3 pg/mL, P < 0.0001) while non-significant differences were observed with IL-10 (2.0 ± 1.0 versus 2.8 ± 1.5 pg/mL, P = 0.675) concentrations than those without periodontitis. PISA was independently associated with CGRP in patients with chronic migraine (β = 0.003; 95% confidence interval: 0.001 to 0.006, P = 0.031). PISA correlated positively with CGRP (r = 0.236; P = 0.017) and IL-6 (r = 0.262; P = 0.008) in chronic migraine.Conclusions: Periodontal inflammation is associated with increased circulating levels of CGRP in chronic migraineurs. Elucidating the exact mechanisms through which periodontitis and CGRP are linked in these patients deserves further investigation. [ABSTRACT FROM AUTHOR]

Here we introduce a guide how to visualize nervous elements in tendons. This guide combines cryo-embedding, immunofluorescence, and confocal laser scanning microscopy. Following this guide, we demonstrate that it is possible to obtain high quality, multicolored fluorescence images of the tendon innervation. Our optimized approach might be a convenient research tool to visualize the heterogeneity of tendon innervation with high accuracy. Tendon pathologies are common and several data suggests that the peripheral nervous system is involved in this disorder. Immunohistochemistry (IHC) is one of the pillars to characterize nervous structures and their implication in the pathogenesis of chronic tendon pain. Most commonly, formalin-fixed, paraffin-embedded (FFPE) tendons are used for immunohistochemical characterization of the innervation. However, FFPE specimens exhibit major disadvantages: First, antigens (proteins) are masked and antigen retrieval is necessary to restore antigenicity. Second, FFPE specimens involve immunolabeling with enzyme-conjugated antibodies but this approach has limitations when multiple antigens are of interest simultaneously. Consequently, there is a demand in the orthopedic community for an alternative immunohistochemical approach to visualize tendon innervations. Here, we present a guide how to visualize tendon innervation. This guide couples paraformaldehyde fixation, cryo-embedding, immunofluorescence, and confocal laser scanning microscopy. We demonstrate the utility of our approach in the long head of the biceps tendon. For nerve fiber characterization, we used different neuronal markers including antibodies against neurofilament, protein gene product 9.5, calcitonin gene related peptide, and substance P. We show that it is possible to collect high quality, multicolor images of the innervation pattern of tendons. To map immunolabeled structures and the anatomical structures of the tendon fluorescence images and bright field images were merged. For the orthopedic community our approach might be a convenient research tool to simultaneously utilize multiple neuronal markers on the same tissue section and to define with greater accuracy the heterogeneity of tendon innervation. [ABSTRACT FROM AUTHOR]

Although chronic pain after amputation is frequent, the underlying mechanisms are still not well understood. It is widely accepted that the pathogenesis of postamputation pain is multifactorial, with both peripheral and central mechanisms playing an essential role. However, recent studies suggest that the immune system plays an important role in different neuropathic pain conditions, including postamputation pain. Eleven amputees were included in this clinical study. Information on the type and intensity of spontaneous postamputation pain was obtained and evoked pain responses for brush, cold, and warm allodynia and pinprick hyperalgesia were determined. In addition, skin biopsies were taken from the amputated site and a contralateral control site and analysed for possible markers of pain: IbA1 (macrophages), calcitonin gene-related peptide (CGRP), and substance P (SP). Irrespectively of the type and intensity of postamputation pain, no differences were found in IbA1, CGRP, and SP levels between the amputated site and the control site. Although no differences between the sites were seen in this study, this new method seems promising for our understanding of skin changes in amputees. In future studies, staining for other cytokines and inflammatory mediators in skin biopsies could provide new insight into the mechanisms of postamputation pain. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This paper aims to establish the rabbit model of traumatic brain injury (TBI) complicated with tibial fracture and to investigate the expressions and significance of calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF) in cerebrospinal fluid (CSF) and serum. MATERIALS AND METHODS: 60 rabbits were randomly divided into control group, TBI group, fracture group (F group), and TBI complicated with fracture group (TBI+F group), with 15 white rabbits in each group. After modeling, the expression levels of CGRP and NGF in the CSF, and serum were detected. At the 7th week after the operation, X-ray was used to evaluate the healing of fracture rabbits. RESULTS: Serum NGF content was compared among groups at the same time point. TBI+F group had significantly higher serum NGF content than the other three groups at each time point after the operation (p<0.05). From the 3rd day after the operation, TBI group and F group had significantly higher serum NGF content than control group (p<0.05). On the 7th and 14th days after the operation, TBI group had significantly higher serum NGF content than the F group (p<0.05). The CSF NGF content in TBI group and TBI+F group showed an upward trend, and it was higher in TBI+F group and TBI group than that in F group and control group from the 7th day (p<0.05). On the 0th and 3rd days, TBI+F group had significantly higher serum NGF content than the other three groups (p<0.05). TBI+F group had a significantly higher healing number than F group on the 14th day (p<0.05). CONCLUSIONS: NGF and CGRP are mainly present in the CSF. When TBI complicated with F occurs, the serum NGF and CGRP increase, which may be involved in the fracture healing. [ABSTRACT FROM AUTHOR]

Copyright of Canadian Journal of Veterinary Research / Revue Canadienne de Recherche Vétérinaire is the property of Canadian Veterinary Medical Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Around the globe, worsening air pollution is spawning major public health and environmental concerns, especially in the poorest and most populous cities. As a major secondary air pollutant, ozone is a potential risk factor for exacerbated asthma, although the underlying mechanisms remain uncertain. In this study, we aim to investigate the role of ozone on asthma exacerbation using a classic asthmatic model with allergic airway inflammation by treating Balb/c mice with ovalbumin (OVA). Our study shows ozone exposure significantly exacerbated OVA-induced asthmatic phenotypes, including serum immunoglobulin, Th cytokines, inflammatory cell counts, mucus production, airway remodeling, and airway hyper-responsiveness (AHR). Interestingly, expression of transient receptor potential cation channel subfamily V member1 (TRPV1) was also significantly elevated in ozone-exacerbated asthmatic mice and that treatment with TRPV1 antagonist effectively suppressed AHR, airway inflammation and remodeling. The underlying mechanisms of these effects may be associated with suppression of neuropeptide calcitonin gene-related peptide (CGRP) and thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine. Base on the role of TRPV1 in allergic asthma, this study further revealed that inhibition of TRPV1 by TRPV1 antagonist has significant anti-inflammatory effects on ozone-induced asthma exacerbation in this study. Induction of TRPV1 expression may be an important mechanism underlying the increased risks for asthma after exposure to environmental pollutants. Graphical abstract Image 1 Highlights • TRPV1 was significantly elevated in ozone-exacerbated asthmatic mice. • TRPV1 antagonist effectively suppressed ozone induced exacerbated effect. • The underlying mechanisms may be associated with CGRP and TSLP. [ABSTRACT FROM AUTHOR]

HIV-1 mucosal transmission in genital epithelia occurs through infection of Langerhans cells and subsequent transinfection of CD4+ T cells. We previously reported that the vasodilator neuropeptide calcitonin gene-related peptide (CGRP), secreted upon activation of sensory peripheral neurons that innervate all mucosal epithelia, significantly inhibits transinfection. To investigate the association between CGRP and HIV-1 during infection, we evaluated circulating CGRP levels in HIV-1-infected patients. Plasma was obtained from combination antiretroviral therapy (cART)-naive or cART-treated patients with primary/acute (PHI) or chronic (CHI) HIV-1 infection, as well as from individuals who naturally control HIV-1 infection, namely exposed seronegatives (ESNs), elite controllers (ECs), and long-term nonprogressors (LTNPs). CGRP plasma levels were measured using an enzyme immunoassay. Compared with healthy HIV-1-negative controls, CGRP plasma levels significantly decreased in PHI patients and even further in CHI patients, but remained unchanged in ESNs, ECs, and LTNPs. Moreover, CGRP plasma levels were restored to baseline upon cART in both PHI and CHI. Finally, CGRP plasma levels directly correlated with CD4+ T cell counts and inversely with viral loads. Altogether, CGRP could serve as a novel diagnostic plasma biomarker for progression of HIV-1 infection. Moreover, administration of CGRP to cART-naive HIV-1-infected patients, to compensate for CGRP decline, could help controlling on-going HIV-1 infection. [ABSTRACT FROM AUTHOR]

The aim of the present study was to identify the relationship between the expression of calcitonin gene-related peptide (CGRP) and the responses of pulp sensitivity tests in healthy pulps and irreversible pulps by performing a cross-sectional study on patients. Two hundred subjects were evaluated. A total of 75 subjects complied with the criteria. The participants were divided into two groups: a) Healthy pulp (subjects [n = 35] having posterior teeth with clinically normal pulp tissue), and b) Irreversible pulpitis (subjects [n = 40] having posterior teeth with irreversible pulpitis). All participants were evaluated using the following variables: a) medical and dental history, b) pulp sensitivity tests, c) expression of CGRP by the enzyme-linked immunosorbent assay (ELISA), and d) expression levels of mRNA CGRP and mRNA CGRP receptor genes. We determined that the responses of the cold test between 4 and ≥12 s presented a higher average of the expression of CGRP in the group having irreversible pulpitis (p = 0.0001). When we compared the groups with the value of the electrical impulse, we found statistically significant differences (p = 0.0001), observing positive responses to the test with electrical impulses of 7 to 10, with an average of 72.15 ng/mL of CGRP in the irreversible pulpitis group. High values of CGRP expression were observed in that group in the responses of pulp sensitivity. [ABSTRACT FROM AUTHOR]

Abstract Calcitonin gene-related peptide-α (CGRPα) is a neurotransmitter that is related to bone formation during development. However, CGRP expression is not well known to affect the formation of teeth during development. During tooth germ development, the relationships among CGRPα, calcitonin receptor-like receptor (CRLR), amelogenin (AMELX), dentin sialophosphoprotein (DSPP), osteopontin (OPN) and osteocalcin (OCN) are unclear despite various tooth and osteogenesis markers. Our real-time RT-PCR results showed that the expression levels of CGRPα mRNA gradually decreased, in contrast to the mRNA abundances of CRLR, AMELX, DSPP, OPN, and OCN, which rapidly increased from E14.5 to P1 in the mandible. In situ hybridization using an antisense probe for CGRPα mRNA showed significant localized expression levels around the tooth bud at E14.5 and epithelial cells near the dental ledge and outer and inner enamel epithelium at E17.5 compared to those at P1. The localization of the anti-CGRPα antibody reaction revealed a strong positive reaction at the surface layer of oral epithelial cells at E14.5 and oral epithelial cells of the dental lamina around the dental ledge depression in the mandible of E17.5 mice using immunohistochemical methods The different anti-CGRPα reaction revealed its important roles during tooth formation at the postnatal stage. CGRPα mRNA was also detected in the interactions of tooth germ with the formation of odontoblast and amelobast layers from dental papilla and inner enamel epithelium. CGRPα may also be related to tooth germ development. Furthermore, CGRPα is an important tooth and bone formation marker, and bone cells provide further evidence of a role in mandibular development in contrast to inflammatory systems. [ABSTRACT FROM AUTHOR]

Introduction: Mal de Debarquement Syndrome (MdDS) is a condition characterized by a sensation of motion in the absence of a stimulus, which presents with two subtypes depending on the onset: Motion-Triggered, and Spontaneous or Non-Motion Triggered. MdDS predominantly affects women around 40-50 years of age and a high number of patients report associated disorders, such as migraine and depression. The pathophysiology of MdDS is unclear, as is whether there are predisposing factors that make individuals more vulnerable to developing the condition. Hormonal changes in women similarly to what observed in migraineous patients, as well as depression disorder, have been examined as potential key factors for developing MdDS. Studies on migraine and depression have revealed correlations with hormonal fluctuations in females as well as aberrant levels of some key neurotransmitters such as Gamma-Aminobutyric Acid (GABA) and inflammatory neuropeptides like Calcitonin Gene-Related Peptide (CGRP). Consequently, this manuscript aims to propose a new hypothesis on the predisposing factors for MdDS and a new concept that could contribute to the understanding of its pathophysiology.New Hypothesis: Recent findings have demonstrated a role for hormonal influences in MdDS patients, similar to previous observations in patients with depression and migraine. We hypothesize the involvement of gonadal hormones and aberrant neurotransmitter levels, including the GABAergic and serotonergic systems, in MdDS pathophysiology. Our theory is that certain individuals are more vulnerable to develop MdDS during specific gonadal hormonal phases. Furthermore, we hypothesize that it may be possible to identify these individuals by measurement of an existing imbalance of these neurotransmitters or inflammatory neuropeptides like CGRP.Further Evaluation Of the Hypothesis: According to one theory, MdDS is considered as a maladaptation of the Vestibular Ocular Reflex (VOR) and velocity storage. When considering this theory, it is essential to highlight that the brainstem nuclei involved in the VOR and the velocity storage include GABAb sensitive neurons, which appear to produce inhibitory control of velocity storage. Responses of these GABAb sensitive neurons are also modulated by CGRP. Thus an alteration of the GABAergic network by imbalances of inhibitory neurotransmitters or CGRP could influence signal integration in the velocity storage system and therefore be directly involved in MdDS pathophysiology.Consequence Of the Hypothesis and Future Studies: A hormonal and neurotransmitter imbalance may act to predispose individuals in developing MdDS. Future studies should focus on the hormonal influences on neurotransmitters (e.g. GABA) and on the trial of CGRP antagonist drugs for the treatment of MdDS patients. [ABSTRACT FROM AUTHOR]

Adriamycin is a potent anthracycline-type antitumor agent, but it also exerts potentially serious side effects due to its cardiotoxic and neurotoxic propensity. Multiple impairments in sensory nerve functions have been recently reported in various rat models. The present experiments were initiated in an attempt to reveal adriamycin-induced changes in sensory effector functions of chemosensitive meningeal afferents. Meningeal blood flow was measured with laser Doppler flowmetry in the parietal dura mater of adult male Wistar rats. The dura mater was repeatedly stimulated by topical applications of capsaicin, a transient receptor potential vanilloid 1 (TRPV1) receptor agonist, or acrolein, a transient receptor potential ankyrin 1 (TRPA1) receptor agonist, which induce the release of calcitonin gene-related peptide (CGRP) from meningeal afferents. The blood flow increasing effects of CGRP, histamine, acetylcholine and forskolin were also measured. Capsaicin- and acrolein-induced CGRP release was measured with enzyme-linked immunoassay in an ex vivo dura mater preparation. TRPV1 content of trigeminal ganglia and TRPV1-, CGRP- and CGRP receptor component-immunoreactive structures were examined in dura mater samples obtained from control and adriamycin-treated rats. The vasodilator effects of capsaicin, acrolein and CGRP were significantly reduced in adriamycin-treated animals while histamine-, acetylcholine- and forskolin-induced vasodilatation were unaffected. Measurements of CGRP release in an ex vivo dura mater preparation revealed an altered dynamic upon repeated stimulations of TRPV1 and TRPA1 receptors. In whole-mount dura mater preparations immunohistochemistry revealed altered CGRP receptor component protein (RCP)-immunoreactivity in adriamycin-treated animals, while CGRP receptor activity modifying protein (RAMP1)-, TRPV1- and CGRP-immunostaining were left apparently unaltered. Adriamycin-treatment slightly reduced TRPV1 protein content of trigeminal ganglia. The present findings demonstrate that adriamycin-treatment alters the function of the trigeminovascular system leading to reduced meningeal sensory neurogenic vasodilatation that may affect the local regulatory and protective mechanisms of chemosensitive afferents leading to alterations in tissue integrity. [ABSTRACT FROM AUTHOR]

Background The pathogenesis of chronic pancreatitis (CP) is a complex process of interaction between tissue injury and repair, which involves microcirculatory disturbance. Amygdalin, an effective component extracted from Semen Persicae (a kind of Chinese herbal medicine), can decrease blood viscosity and improve microcirculation. In this study, we investigated the therapeutic effects of amygdalin on pancreatic fibrosis in rats with CP. Methods The rat CP model was induced by injecting dibutyltin dichloride (DBTC) into the right caudal vein. Amygdalin was administrated via the penile vein at a dose of 10 mg/(kg d) from the next day, after the induction of CP, once a day for the previous 3 days, and then once every 2 days, until the end of the experiment. Body weight was observed every 7 days. Pancreatic blood flow and histopathological changes were assessed at 28 days. The activation of pancreatic stellate cells (PSCs) was estimated by the expression of α-smooth muscle actin (α-SMA). At the same time, the expression of platelet-derived growth factor-BB (PDGF-BB), transforming growth factor β-1 (TGFβ-1), endothelin-1 (ET-1), and calcitonin gene-related peptide (CGRP) of pancreatic tissues were detected. Results Treatment of CP rats with amygdalin improved body weight and pancreatic blood flow, as well as alleviated pancreatic fibrosis and acinar destruction, accompanied by the down-regulation of the expressions of α-SMA, PDGF-BB, TGFβ-1, and ET-1, and the up-regulation of the CGRP's expression. Conclusion Amygdalin could reduce the production of pro-fibrotic cytokines, inhibit the activation of PSCs, and attenuate pancreatic fibrosis in a rat with CP. The mechanism probably includes improving microcirculatory disturbance by regulating the production of ET-1 and CGRP. [ABSTRACT FROM AUTHOR]

Objective The potential for brown adipose tissue (BAT) to be targeted as a therapeutic option to combat obesity has been heightened by the discovery of a brown–like form of inducible “beige” adipose tissue in white fat which has overlapping structural and functional properties to “classical” BAT. The likelihood that both beige and brown fat are recruited functionally by neural mechanisms, taken together with the lack of a detailed understanding of the nature of changes in the nervous system when white adipose tissue (WAT) is transformed to brown, provides the impetus for this study. Here, we aim to identify whether there is a shift in the gene expression profile in neurons directly innervating inguinal white adipose tissue (iWAT) that has undergone “beiging” to a signature that is more similar to neurons projecting to BAT. Methods Two groups of rats, one housed at thermoneutrality (27 °C) and the other exposed to cold (8 °C) for 7 days, were killed, and their T13/L1 ganglia, stellate ganglion (T1/T2), or superior cervical ganglion (SCG, C2/3) removed. This approach yielded ganglia containing neurons that innervate either beiged white fat (8 °C for 7 days), inguinal WAT (27 °C for 7 days), BAT (both 27 °C and 8 °C for 7 days) or non-WAT (8 °C for 7 days), the latter included to isolate changes in gene expression that were more aligned with a response to cold exposure than the transformation of white to beige adipocytes. Bioinformatics analyses of RNA sequencing data was performed followed by Ingenuity Pathway Analysis (IPA) to determine differential gene expression and recruitment of biosynthetic pathways. Results When iWAT is “beiged” there is a significant shift in the gene expression profile of neurons in sympathetic ganglia (T13/L1) innervating this depot toward a gene neurochemical signature that is similar to the stellate ganglion projecting to BAT. Bioinformatics analyses of “beiging” related genes revealed upregulation of genes encoding neuropeptides proopiomelanocortin (POMC) and calcitonin-gene related peptide (CGRP) within ganglionic neurons. Treatment of differentiated 3T3L1 adipocytes with αMSH, one of the products cleaved from POMC, results in an elevation in lipolysis and the beiging of these cells as indicated by changes in gene expression markers of browning ( Ucp1 and Ppargc1a ). Conclusion These data indicate that, coincident with beiging, there is a shift toward a “brown-like” neurochemical signature of postganglionic neurons projecting to inguinal white fat, an increased expression of POMC, and, consistent with a causative role for this prohormone in beiging, an αMSH-mediated increase in beige gene markers in isolated adipocytes. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effect of a placebo, intracanal diode laser application, and low-level laser therapy (LLLT) on the change of the total amount of calcitonin gene-related peptide (CGRP) in the gingival crevicular fluid (GCF) (split-mouth study design). GCF sampling was performed on a contralateral tooth and experimental tooth (root canal-treated tooth) of thirty-nine patients. The patients were divided into three groups (n = 13), as follows: placebo (mock laser application), intracanal laser application, and LLLT. GCF sampling was repeated at the same sites (experimental and control teeth) one week after root canal treatment. The data were analyzed using the Pearson's correlation analysis and the independent-samples t-tests (p=0.05). In the placebo group, the total CGRP level changes in the GCF before and after treatment was significantly higher for experimental teeth than for control teeth (p<0.05). However, there was no significant difference between experimental and control teeth in the intracanal laser application and LLLT groups (p > 0.05). Intracanal laser application and low-level laser therapy have immunomodulation effects linked to the modulation of the total amount of CGRP in the GCF. [ABSTRACT FROM AUTHOR]

Recent experimental evidences from cellular systems and from mammalian and non-mammalian animal models highlight novel functions for the aryl hydrocarbon/dioxin receptor (AhR) in maintaining cell differentiation and tissue homeostasis. Notably, AhR depletion stimulates an undifferentiated and pluripotent phenotype likely associated to a mesenchymal transition in epithelial cells and to increased primary tumorigenesis and metastasis in melanoma. In this work, we have used a lung model of epithelial regeneration to investigate whether AhR regulates proper tissue repair by adjusting the expansion of undifferentiated stem-like cells. AhR-null mice developed a faster and more efficient repair of the lung bronchiolar epithelium upon naphthalene injury that required increased cell proliferation and the earlier activation of stem-like Clara, Basal and neuroepithelial cells precursors. Increased basal content in multipotent Sca1 + /CD31 − /CD4 − cells and in cells expressing pluripotency factors NANOG and OCT4 could also improve re-epithelialization in AhR-null lungs. The reduced response of AhR-deficient lungs to Sonic Hedgehog ( Shh ) repression shortly after injury may also help their improved bronchiolar epithelium repair. These results support a role for AhR in the regenerative response against toxins, and open the possibility of modulating its activation level to favor recovery from lesions caused by environmental contaminants. [ABSTRACT FROM AUTHOR]

Background & Aims Little is known about the causes of heartburn in patients with gastro-esophageal reflux disease. Visible epithelial damage is seldom associated with symptom severity, evidenced by the significant symptom burden in patients with nonerosive reflux disease (NERD) compared with patients with erosive reflux disease (ERD) or Barrett’s esophagus (BE). We studied the distribution of mucosal nerve fibers in patients with NERD, ERD, and BE, and compared the results with those of healthy subjects. Methods We performed a prospective study of 13 patients with NERD, 11 patients with ERD, and 16 patients with BE undergoing endoscopic evaluation in the United Kingdom or Greece. Biopsies were obtained from the proximal and distal esophageal mucosa of patients with NERD, from the distal esophageal mucosa of patients with ERD, and the distal-most squamous epithelium of patients with BE. These were examined for the presence and location of nerve fibers that reacted with a labeled antibody against calcitonin gene-related peptide (CGRP), a marker of nociceptive sensory nerves. The results were compared with those from 10 healthy volunteers (controls). Results The distribution of CGRP-positive nerves did not differ significantly between the distal esophageal mucosa of controls (median, 25.5 cell layers to surface; interquartile range [IQR], 21.4–28.8) vs patients with ERD (median, 23 cell layers to surface; IQR, 16–27.5), or patients with BE (median, 21.5 cell layers to surface; IQR, 16.1–27.5). However, CGRP-positive nerves were significantly more superficial in mucosa from patients with NERD—both distal (median, 9.5 cell layers to surface; IQR, 1.5–13.3; P < .0001 vs ERD, BE, and controls) and proximal (median, 5.0 cell layers to surface; IQR, 2.5–9.3 vs median 10.4 cell layers to surface; IQR, 8.0–16.9; P = .0098 vs controls). Conclusions Proximal and distal esophageal mucosa of patients with NERD have more superficial afferent nerves compared with controls or patients with ERD or BE. Acid hypersensitivity in patients with NERD might be partially explained by the increased proximity of their afferent nerves to the esophageal lumen, and therefore greater exposure to noxious substances in refluxate. [ABSTRACT FROM AUTHOR]

Oxidative stress also plays an important role in the pathogenesis of diabetic neuropathy (DN). Both resveratrol (RES) and exercise (EX) have potent anti-oxidative benefits. Low levels of nerve growth factor (NGF) and SIRT1 (a member of sirtuin family) have been reported in patients with DN. The current study has been designed to investigate the role of serum NGF and SIRT1 on DN-induced hyperalgesia and motor incoordination and to evaluate the possible protective role of RES and/or EX. A total of 40 male adult albino rats divided into five groups; control, DN, DN + RES, DN + EX, and DN + RES and EX. DN was confirmed by sensorimotor disturbance and diminished nerve conduction velocity (NCV). NGF and SIRT1 levels were measured by western blot. Calcitonin gene-related peptide (CGRP) was measured by PCR. Myofibrillar degeneration and inflammation scores were revealed via H&E microscopic analysis of the gastrocnemius muscle. Immunohistochemical evaluation of caspase3 and TNF-α was performed in the lumber segment of spinal cord and gastrocnemius muscle sections. Ultrastructural evaluation of sciatic nerve axonal degeneration has also been assessed. DN group showed decreased SIRT1 level, decreased NGF level and correlated with CGRP level and Na+/K+ ATPase. Treatment with RES and/or EX resulted in improvement of sensorimotor disturbance. DN characterized by reduced SOD level, whereas RES and/or EX could limit oxidative damage by up-regulation Bcl2, Akt and GAP-43 and down-regulation of caspase3 and TNF-α. In conclusion, increased level of SIRT1and NGF by incorporation of RES (natural supplementation) and EX (life style modification) could improve the neuroinflammatory state in DN. • Resveratrol and exercise training could prevent the diabetes-induced histological and ultrastructural neuronal changes. • They also alleviated the immunohistochemical expression of TNF-α and caspase 3 in the lumbar spinal cord and muscle. • Those effects were achieved through SIRT1-mediated antioxidant mechanism and modulation of SIRT1/NGF/GAP43 signals. [ABSTRACT FROM AUTHOR]

We have previously shown that topical opioids including morphine and its congeners promote healing of full thickness ischemic wounds in rats. We examined the contribution of mu opioid receptor (MOPr)-mediated healing of full thickness ischemic wounds using MOPr and delta or kappa opioid receptor knockout (KO) mice. Wound closure in the early (day 5) as well as later phases was delayed in topical morphine or PBS-treated MOPr-KO mice compared with reciprocal treatments of wounds in wild-type (WT) mice. MOPr expression was significantly upregulated at 30 min in the wound margins and colocalized with wound margins and vasculature in the epidermal and dermal layers of the skin. We next examined whether neuropeptide expression was involved in the mechanism of MOPr-mediated wound closure. Substance P (SP) and calcitonin gene-related peptide immunoreactivity (ir) was significantly increased in the skin of MOPr-KO mice as compared with WT mice. Neuropeptide-ir was increased significantly in PBS-treated wounds of MOPr and WT mice, but morphine treatment reduced neuropeptide immunoreactivity in both as compared with PBS. Wounding of keratinocytes led to the release of opioid peptide beta-endorphin (β-END) in conditioned medium, which stimulated the proliferation of endothelial cells. MOPr-selective (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2, CTOP) and nonselective OPr antagonist naloxone-inhibited endothelial proliferation induced by wounded keratinocyte-conditioned medium. In addition, accelerated wound area closure in vitro by morphine was suppressed by methylnaltrexone, a nonselective OPr antagonist with high affinity for MOPr. Morphine and its congeners stimulated the proliferation of endothelial cells from WT mice but not those from MOPr-KO mice. Furthermore, morphine-induced mitogen-activated protein kinase/extracellular signal-regulated kinase phosphorylation in endothelial cells was significantly decreased in MOPr-KO mice as compared with WT mice. Collectively, these data suggest that MOPr plays a critical role in the proliferation phase with the formation of granulation tissue during wound healing. [ABSTRACT FROM AUTHOR]

Purpose We measured urinary biomarker levels in women with refractory urgency urinary incontinence and controls at baseline and 6 months after treatment with sacral neuromodulation or intradetrusor injection of onabotulinumtoxinA. We also assessed the association of baseline biomarkers with posttreatment urgency urinary incontinence episodes and overactive bladder symptom bother outcomes. Materials and Methods First morning urine samples were collected from consented trial participants and age matched women without urgency urinary incontinence. Biomarkers reflecting general inflammation, neuroinflammation, afferent neurotransmitters and tissue remodeling were measured using standardized enzyme-linked immunosorbent assay and activity assays as appropriate. Symptom bother was assessed by the overactive bladder questionnaire and urgency urinary incontinence episodes were determined by bladder diary. Linear models were used to examine differences in mean biomarker levels and the change in urgency urinary incontinence episodes and symptom bother between baseline and 6 months. Modest evidence of a potential association was represented by p ≤0.01 and p ≤0.004 represented moderate evidence of an association with outcomes. Results Baseline biomarker levels differed little between cases and controls except tropoelastin (p = 0.001) and N-terminal telopeptide collagen type 1 (p <0.001). Changes in biomarker levels 6 months after intervention included decreases in collagenase (p <0.001) in both treatment groups and increases in interleukin-8 (p = 0.002) and matrix metalloprotease-9 (p <0.001) in the onabotulinumtoxinA group. Higher baseline calcitonin gene-related peptide across both treatments (p = 0.007) and nerve growth factor in the onabotulinumtoxinA arm (p = 0.007) were associated with less reduction in overactive bladder symptom bother. Conclusions Refractory urgency urinary incontinence is a complex condition. These data suggest that matrix remodeling and neuropeptide mediation may be involved in its pathophysiological mechanisms and response to treatment. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This research attempts to identify the part the hippocampus plays in accelerated fracture-healing after traumatic brain injury as well as to test functions of calcitonin gene-related peptide (CGRP) during this process. MATERIALS AND METHODS: Experiments were carried out on Male Sprague-Dawley rats that were split into four groups at random: TBI-fracture group, fracture-only group, TBI-only group, and control group. In the first week, blood specimen would be drawn from rats among the groups except those of the control group at threetime points (24, 72 and 168 hours) post-damage. These rats would be assessed from the neurological perspective based on their grades of performance in a sequence of tests 24 hours before and 12 hours after brain injury. Blood samples were also taken from the control group 24 hours before the injury, and whole brain tissues in the injured groups were harvested at 72 and 168 hours post-injury. We compared the serum CGRP concentration, the distribution of CGRP, the CGRP expression, and the expression of CGRP in the hippocampus, the expression of CGRP in the hippocampus, the expression of CGRP in the hippocampus, and the expression of CGRP in the brain by immunohistochemistry, Western blotting, RTOf CGRP RNA expression levels. RESULTS: Neurological examinations suggested that the functions of the cerebral cortex, cerebellum, and brain stem showed significant differences pre- and post-injury (p < 0.001). ELISA analysis indicated a great density of CGRP in TBI-fracture group at different time points. Furthermore, in the TBI-fracture group, CGRP in both hippocampus and the whole brain showed a noticeable augment in RT-PCR and western blot analysis at 72 and 168 h post-injury, and only in this group, immunohistochemistry analysis indicated that CGRP was present in the hippocampus at 168 hours post-injury. CONCLUSIONS: We observed that the hippocampus and CGRP were responsible for quick bone-healing mechanisms. We suggest a role for the hippocampus in accelerated fracture healing. CGRP expression, as determined by IHC, cannot be observed in other groups, indicating that the hippocampus may be the specific component of the brain that responds to "big stress". [ABSTRACT FROM AUTHOR]

Background: Swimming is commonly considered to be an efficient rehabilitation exercise to treat peripheral nerve injury. However, the most effective resistance level and exercise duration is still unclear. We investigated the effects and mechanisms of swimming at various exertion levels in a rat sciatic nerve transection model. Methods: Sciatic nerve transection rats were randomized into the following four groups based on swimming duration (from the 7th day to the 28th day post-surgery): sedentary control group (SC), S10 group (10 min/3 times/week), S20 group (20 min/3 times/week), and S30 group (30 min/3 times/week) (n = 10 each). Axon regeneration, electrophysiological properties, muscular weights, macrophage infiltration, and nerve repair associated maker, calcitonin gene-related peptide (CGRP), were measured. Results: Dramatic higher successful percentages of nerve regeneration across the 10-mm gaps in swimming groups compared to the SC group. Total area of nerve regeneration significantly improved in the S10 group; however, electrophysiological properties, muscular weights, and macrophage infiltration in the regenerated nerves of rats did not differ significantly between the various exercise groups. CGRP expression was significantly increased in the spinal cord of rats in the S20 group. Conclusions: Our data indicated that CGRP-related axonal regeneration improved significantly with moderate swimming. These results should inspire new studies in physiotherapeutic practice for related human treatment. [ABSTRACT FROM AUTHOR]

Background Various investigations have demonstrated that calcitonin gene-related peptide (CGRP) plays an important role in mediating ischemic preconditioning. CGRP has been shown to mimic the protective effects of ischemic preconditioning and mitigate ischemia-reperfusion (I/R) injury in the heart, brain, gastrointestinal system, and other tissues. This study aimed to examine whether CGRP, a proven intestinal cytoprotective molecule, exerted its protective effects through modulation of inducible nitride oxide synthase (iNOS) and apoptosis after intestinal I/R injury. Methods This animal study randomly divided 30 rats into the following five groups: (1) the normal control group, (2) the ischemia group with normal saline, (3) the I/R group with normal saline, (4) the ischemia group with CGRP (300 μg/kg), and (5) the I/R group with CGRP (300 μg/kg). Levels of iNOS messenger RNA (mRNA) and protein, and caspase-3 protein were determined by real-time quantitative polymerase chain reaction and Western blotting analyses, respectively. Statistical analysis was performed using analysis of variance with Dunn test. Results The mRNA levels of iNOS increased after the intestinal ischemia or intestinal reperfusion phase ( p < 0.01), and CGRP pretreatment significantly decreased iNOS mRNAs and protein levels ( p < 0.01). The expression protein levels of caspase-3 increased after the intestinal ischemia or intestinal reperfusion phase. CGRP pretreatment significantly decreased the levels of caspase-3 proteins. CGRP intestinal cytoprotection is mediated, in part, by downregulation of expression of iNOS and caspase-3 after intestinal I/R injury. Conclusion The study indicates that the cytoprotective role of CGRP (i.e., antiapoptotic effect) after I/R injury could be via downregulation of iNOS, which may relieve I/R tissue damage by blocking iNOS activity. [ABSTRACT FROM AUTHOR]

Introduction The first objective was to determine correlation among various experimental and clinical pain measurement procedures. The second objective was to evaluate the influence of rotary instrumentation with continuous irrigation on pain and neuropeptide release levels. Methods Forty patients who had preoperative pain at the levels of 3–8 on the visual analogue scale were included. Gingival crevicular fluid (GCF) samples were collected. Patients were randomly assigned to 2 treatment groups, the standard preparation group and the preparation with continuous irrigation group. Apical fluid samples (AFS) were collected after instrumentation. In the second visit, the patients' pain levels were recorded, and GCF and AFS were obtained. Substance P, calcitonin-gene related peptide (CGRP), interleukin (IL)-1β, and IL-10 levels were analyzed from the GCF and AFS samples. For comparison between groups, the Mann-Whitney test was used ( P < .05). Results In terms of clinical data, no significant difference was detected in the first and second sessions between groups. The IL-10 level obtained from AFS significantly decreased in the second session in both groups ( P < .001). Visual analogue scale scores of spontaneous pain correlated with percussion pain positively ( r = 0.718, P < .001). CGRP (GCF) (second session) and IL-10 (GCF) (second session) positively correlated with percussion pain ( r = 0.425, P < .01) ( r = 0.379, P < .05). Conclusions Rotary preparation with continuous irrigation has not been more effective than the standard preparation method for reducing pain. Because of determination of the correlation between CGRP and IL-10 with percussion pain, these neuropeptides can be used in further studies. [ABSTRACT FROM AUTHOR]

Introduction Nociceptive neurons play a critical role in the detection of stimuli evoking actual or potential tissue injury. In addition, they are involved in neurogenic inflammation by the peripheral release of neuropeptides such as calcitonin gene-related peptide (CGRP). The dental pulp and periradicular tissues are innervated by capsaicin-sensitive neurons known to release CGRP. However, the role of these capsaicin-sensitive neurons in the development of apical periodontitis is largely unknown. The aim of this study was to evaluate the contribution of peptidergic neurons to the development of apical periodontitis. Methods Neonatal Sprague-Dawley rats were injected with vehicle (control group) or a single subcutaneous capsaicin dose to cause the selective ablation of peptidergic neurons (neonatal capsaicin group). Ablation of capsaicin-sensitive neurons was verified with confocal microscopy, capsaicin-induced eye-wipe nocifensive behavior test, and by measurement of immunoreactive CGRP levels in the dental pulp. Five weeks after ablation, standardized pulp exposures were made in the mandibular left first molars. Mandibles were harvested at 7, 14, 21, and 28 days after pulp exposure and imaged with micro–computed tomography (μCT) to quantify apical lesion volume. Data were analyzed by using 2-way ANOVA analysis with Bonferroni post hoc test. Results Rats in the control group displayed a robust capsaicin-induced nocifensive behavior, which was nearly abolished in the neonatal capsaicin group. In addition, the neonatal capsaicin group showed a significant depletion of susceptible neurons and CGRP in the dental pulp compared with control. Importantly, micro–computed tomography analysis showed larger periradicular lesions at 7 and 14 days after pulp exposure in the neonatal capsaicin group when compared with control. Conclusions Results identify a protective role for capsaicin-sensitive neurons in the initial phase of apical periodontitis. Thus, interventions or disorders that alter activity of capsaicin-sensitive fibers are likely to alter the development of apical periodontitis. [ABSTRACT FROM AUTHOR]

Mast cells (MCs), which are granulated tissue-resident cells of hematopoietic lineage, contribute to vascular homeostasis, innate/adaptive immunity, and wound healing. However, MCs are best known for their roles in allergic and inflammatory diseases, such as anaphylaxis, food allergy, rhinitis, itch, urticaria, atopic dermatitis, and asthma. In addition to the high-affinity IgE receptor (FcεRI), MCs express numerous G protein–coupled receptors (GPCRs), which are the largest group of membrane receptor proteins and the most common targets of drug therapy. Antimicrobial host defense peptides, neuropeptides, major basic protein, eosinophil peroxidase, and many US Food and Drug Administration–approved peptidergic drugs activate human MCs through a novel GPCR known as Mas-related G protein–coupled receptor X2 (MRGPRX2; formerly known as MrgX2). Unique features of MRGPRX2 that distinguish it from other GPCRs include their presence both on the plasma membrane and intracellular sites and their selective expression in MCs. In this article we review the possible roles of MRGPRX2 on host defense, drug-induced anaphylactoid reactions, neurogenic inflammation, pain, itch, and chronic inflammatory diseases, such as urticaria and asthma. We propose that host defense peptides that kill microbes directly and activate MCs through MRGPRX2 could serve as novel GPCR targets to modulate host defense against microbial infection. Furthermore, mAbs or small-molecule inhibitors of MRGPRX2 could be developed for the treatment of MC-dependent allergic and inflammatory disorders. [ABSTRACT FROM AUTHOR]

Purpose Chronic prostatitis/chronic pelvic pain syndrome causes symptoms that include the frequent and urgent need to urinate, pain or burning during urination and pain radiating to the back, abdomen and/or colorectum. These bladder symptoms suggest that chronic prostatitis/chronic pelvic pain syndrome is associated with sensitization of adjacent organs, termed cross-organ sensitization. The objective of this study was to determine the extent of 1) changes in immunomodulatory mediators in the prostate and bladder after inflammation of the prostate and 2) bladder function and bladder afferent sensitization. Materials and Methods Prostate and bladder histology, immunohistochemistry and expression of immunomodulatory targets were examined weekly after zymosan or vehicle was injected in the dorsal lobe of the mouse prostate. Cystometry, bladder and bladder afferent sensitivity were also assessed weekly. Results Prostate inflammation induced significant up-regulation in proinflammatory and anti-inflammatory cytokines TNF-α (tumor necrosis factor-α) and IL-10 (interleukin-10), growth factor NGF (nerve growth factor), and T-lymphocyte markers FoxP3, CD4 and CD8 in the prostate and the bladder. Notably, prostatitis significantly increased urinary voiding frequency, induced hypersensitivity to bladder distension and sensitized bladder afferents. We also examined sensory (afferent) co-innervation by injecting retrograde tracers DiI and Fast Blue in the bladder wall and the prostate, respectively. This showed that a significant proportion (approximately 17%) of dorsal root ganglion afferent somata contained tracers from the bladder and the prostate. Conclusions These observations support an afferent contribution to chronic prostatitis/chronic pelvic pain syndrome and cross-organ sensitization from prostate to bladder. [ABSTRACT FROM AUTHOR]

A large and growing portion of the human population, especially in developed countries, suffers 1 or more chronic, often quite burdensome ailments which either are overtly inflammatory in nature or are suspected to be of inflammatory origin, but for which investigations to date have failed to identify specific causes, let alone unifying mechanisms underlying the multiple such ailments that often afflict such patients. Relatively recently described as a non-neoplastic cousin of the rare hematologic disease mastocytosis, mast cell (MC) activation syndrome-suspected to be of greatly heterogeneous, complex acquired clonality in many cases-is a potential underlying/unifying explanation for a diverse assortment of inflammatory ailments. A brief review of MC biology and how aberrant primary MC activation might lead to such a vast range of illness is presented. [ABSTRACT FROM AUTHOR]

Pain is a complex sensation that may be protective or cause undue suffering and loss of function, depending on the circumstances. Peripheral nociceptor neurons (PNs) innervate most tissues, and express ion channels, nocisensors, which depolarize the cell in response to intense stimuli and numerous substances. Inflamed tissues manifest inflammatory hyperalgesia in which the threshold for pain and the response to painful stimuli are decreased and increased, respectively. Constituents of the inflammatory milieu sensitize PNs, thereby contributing to hyperalgesia. Polyunsaturated fatty acids undergo enzymatic and free radical-mediated oxygenation into an array of bioactive metabolites, oxygenated polyunsaturated fatty acids (oxy-PUFAs), including the classic eicosanoids. Oxy-PUFA production is enhanced during inflammation. Pioneering studies by Vane and colleagues from the early 1970s first implicated classic eicosanoids in the pain associated with inflammation. Here, we review the production and action of oxy-PUFAs that are not classic eicosanoids, but nevertheless are produced in injured/ inflamed tissues and activate or sensitize PNs. In general, oxy-PUFAs that sensitize PNs may do so directly, by activation of nocisensors, ion channels or GPCRs expressed on the surface of PNs, or indirectly, by increasing the production of inflammatory mediators that activate or sensitize PNs. We focus on oxy-PUFAs that act directly on PNs. Specifically, we discuss the role of arachidonic acid-derived 12S-HpETE, HNE, ONE, PGA 2 , iso-PGA 2 and 15 d -PGJ 2 , 5,6-and 8,9-EET, PGE 2 -G and 8R,15S-diHETE, as well as the linoleic acid-derived 9-and 13-HODE in inducing acute nocifensive behavior and/or inflammatory hyperalgesia in rodents. The nocisensors TRPV1, TRPV4 and TRPA1, and putative Gαs-type GPCRs are the PN targets of these oxy-PUFAs. [ABSTRACT FROM AUTHOR]