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Background: The demand for essential oils (EOs) has been steadily growing over the years. This is mirrored by a substantial increase in research concerned with EOs also in the field of inflammatory and neuropathic pain. The purpose of this present systematic review and meta-analysis is to investigate the preclinical evidence in favor of the working hypothesis of the analgesic properties of EOs, elucidating whether there is a consistent rational basis for translation into clinical settings.Methods: A literature search has been conducted on databases relevant for medical scientific literature, i.e., PubMed/MEDLINE, Scopus, and Web of Science from database inception until November 2, 2020, following the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) criteria for systematic reviews and meta-analyses.Results: The search was conducted in order to answer the following PICOS (participants/population, interventions, comparisons, outcomes, and study design) question: are EOs efficacious in reducing acute nociceptive pain and/or neuropathic pain in mice experimental models? The search retrieved 2,491 records, leaving 954 studies to screen after the removal of duplicates. The title and abstract of all 954 studies were screened, which left 127 records to evaluate in full text. Of these, 30 articles were eligible for inclusion.Conclusion: Most studies (27) assessed the analgesic properties of EOs on acute nociceptive pain models, e.g. the acetic acid writhings test, the formalin test, and the hot plate test. Unfortunately, efficacy in neuropathic pain models, which are a more suitable model for human conditions of chronic pain, had fewer results (only three studies). Moreover, some methodologies raised concerns in terms of the risk of bias. Therefore, EOs with proven efficacy in both types of pain were corroborated by methodologically consistent studies, like the EO of bergamot, which should be studied in clinical trials to enhance the translational impact of preclinical modeling on clinical pain research.

Supplemental Digital Content is Available in the Text., In humans, proof of long-term efficacy of ketamine treatment in neuropathic pain is lacking. To improve our understanding of ketamine behavior under various administration conditions, we performed a systematic review and meta-analyses of controlled studies on the efficacy of ketamine in mice and rats with a disease model of nerve injury on relief of allodynia. Searches in PubMed and EMBASE identified 31 unique studies. Four meta-analyses were conducted. The first analysis included 19 comparisons on a single ketamine dose and measurement of effect within 3 hours of dosing and showed an appreciable effect (standardized mean difference 1.6, 95% confidence interval 1.1-2.1). Subgroup analyses showed no effect of species, administration route, or dose. A single administration was insufficient to sustain relief of allodynia at 24 or 72 hours after dosing, as observed in our second analysis (7 comparisons) with similar effects in ketamine-treated and control animals. Chronic ketamine administration (9 comparisons) caused profound relief of allodynia when tested during ketamine exposure (effect size 5.1, 3.7-6.5). The final analysis (6 comparisons) showed that chronic administration caused a slow loss of relief of allodynia with 70% loss of effect 24 days after end of treatment. No subgroups analyses were possible in the last 3 meta-analyses due to small group sizes. These results indicate long-term ketamine anti-allodynic effects after chronic exposure (>3 days) but not after a single administration. Given several limitations, extrapolation of the animal data to the human condition is tenuous.

Simple Summary It is difficult to measure pain in horses. As animals are not able to verbalize what they feel, we are left with trying to interpret the different signs that they display when they are in pain. Many of these signs are vague (e.g., not eating their food), but some are more readily identified if the animal moves away or lifts their leg when pressure is applied to a sensitive area. Pressure algometry is a tool used to detect responses to applied mechanical stimuli within painful and nonpainful tissues. Pressure algometry has been used in many different studies, but there is no consensus on how to synthesize this information to better diagnose and treat pain in horses. The purpose of this study was to summarize the results of these studies. Based on that review, we conclude that there is good evidence that pressure algometry is a reliable and objective method to measure pain responses. This information will help to improve the diagnosis and treatment of pain in horses. Abstract The clinical assessment of pain is subjective; therefore, variations exist between practitioners in their ability to identify and localize pain. Due to differing interpretations of the signs or severity of pain equine practitioners may assign varying levels of clinical significance and treatment options. There is a critical need to develop better tools to qualify and quantify pain in horses. Palpation is the most common method to detect local tenderness or sensitivity. To quantify this applied pressure, pressure algometry has been used to gradually apply pressure over specified landmarks until an avoidance response is noted, which is defined as the mechanical nociceptive threshold (MNT). Numerous studies have used pressure algometry in different applications to measure MNTs in horses. There is an acute need to establish normative values within different body regions and to develop standardized methods of testing MNTs to better guide practitioners in the diagnosis and treatment of pain. The aim of this systematic review was to summarize the evidence for the use of pressure algometry in horses. There is good evidence that pressure algometry is a repeatable, semi-objective method that can be used in a wide array of clinical and research applications to assess MNTs in horses.

Pain arising from musculoskeletal disorders such as arthritis is one of the leading causes of disability. Whereas the past 20-years has seen an increase in targeted therapies for rheumatoid arthritis (RA), other arthritis conditions, especially osteoarthritis, remain poorly treated. Although modulation of central pain pathways occurs in chronic arthritis, multiple lines of evidence indicate that peripherally driven pain is important in arthritic pain. To understand the peripheral mechanisms of arthritic pain, various in vitro and in vivo models have been developed, largely in rodents. Although rodent models provide numerous advantages for studying arthritis pathogenesis and treatment, the anatomy and biomechanics of rodent joints differ considerably to those of humans. By contrast, the anatomy and biomechanics of joints in larger animals, such as dogs, show greater similarity to human joints and thus studying them can provide novel insight for arthritis research. The purpose of this article is firstly to review models of arthritis and behavioral outcomes commonly used in large animals. Secondly, we review the existing in vitro models and assays used to study arthritic pain, primarily in rodents, and discuss the potential for adopting these strategies, as well as likely limitations, in large animals. We believe that exploring peripheral mechanisms of arthritic pain in vitro in large animals has the potential to reduce the veterinary burden of arthritis in commonly afflicted species like dogs, as well as to improve translatability of pain research into the clinic.

Effective treatment for many pain disorders is still lacking, which is due to the complexity of pain in general and of the underlying pathology of many pain syndromes in particular. This results in the majority of investigational analgesic drugs failing to reach registration, either due to lack of efficacy, or due to the drug's adverse effect profile. To increase the number of analgesics that reach the patient, it is essential to carefully and rationally plan the clinical development program. By including proof-of-mechanism (PoM) and/or proof-of-concept (PoC) methods in early-phase clinical drug studies, the analgesic drug developer will be better informed regarding the key characteristics of the studied drug, which will aid in making crucial decisions during the development process. Here, we describe the top 10 currently most developed analgesic drug classes, link them mechanistically to appropriate methods to demonstrate PoM and PoC in early-phase clinical trials, and include pros and cons of each of the methods described. Lastly, we discuss how each analgesic drug class requires a tailored experimental approach for proper evaluation of PoM and PoC, and how this can contribute to an efficient and question-based approach in early-phase analgesic drug research.

Background Cebranopadol (a.k.a. GRT-6005) is a dually acting nociceptin/orphanin FQ and opioid receptor agonist that has been recently developed in Phase 2 clinical trials for painful diabetic neuropathy or cancer pain. It also showed analgesic properties in various rat models of pain and had a better safety profile as compared to equi-analgesic doses of morphine. Since antinociceptive properties of cebranopadol have been studied mainly in rat models, in the present study, we assessed analgesic activity of subcutaneous cebranopadol (10 mg/kg) in various mouse pain models. Methods We used models of acute, tonic, and chronic pain induced by thermal and chemical stimuli, with a particular emphasis on pharmacoresistant chronic neuropathic pain evoked by oxaliplatin in which cebranopadol was used alone or in combination with simvastatin. Key results As shown in the hot plate test, the analgesic activity of cebranopadol developed more slowly as compared to morphine (90–120 min vs. 60 min). Cebranopadol displayed a significant antinociceptive activity in acute pain models, i.e., the hot plate, writhing, and capsaicin tests. It attenuated nocifensive responses in both phases of the formalin test and reduced cold allodynia in oxaliplatin-induced neuropathic pain model. Its efficacy was similar to that of morphine. Used in combination and administered simultaneously, 4 or 6 h after simvastatin, cebranopadol did not potentiate antiallodynic activity of this cholesterol-lowering drug. Cebranopadol did not induce any motor deficits in the rotarod test. Conclusion Cebranopadol may have significant potential for the treatment of various pain types, including inflammatory and chemotherapy-induced neuropathic pain.

Supplemental Digital Content is Available in the Text. This experimental highly controlled trial in 20 patients with fibromyalgia shows that the cannabinoid THC, but not CBD, is effective in the treatment of fibromyalgia pain., In this experimental randomized placebo-controlled 4-way crossover trial, we explored the analgesic effects of inhaled pharmaceutical-grade cannabis in 20 chronic pain patients with fibromyalgia. We tested 4 different cannabis varieties with exact knowledge on their ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD) content: Bedrocan (22.4-mg THC

Introduction: The article presents the results of the study of the maximum tolerant dose (MTD) and the analgesic activity of peptide PT1 isolated from Alopecosa marikovskyi spider venom. PT1 is the first compound of polypeptide nature, capable of exerting a selective modulating effect on purinergic P2X3 receptors. Materials and methods: The study was conducted on 174 ICR mice. The analgesic activity of the peptide was evaluated in a thermal hypersensitivity test triggered by CFA and in a model of chemical irritation. Results and discussion: The determined MTD for the peptide PT1 when administered intravenously provides evidence to attribute it to low-toxic compounds. The maximum analgesic activity of PT1 using the biomodel of hypersensitivity induced by CFA when tested 15 minutes after the administration was recorded at doses of 0.1 and 0.5 mg/kg. In the visceral pain test, the maximum analgesic activity 15 minutes after the administration of the chemical stimulus was observed at a dose of 0.01 mg/kg. Conclusions: According to the results of testing peptide PT1, it is shown that it belongs to low-toxic compounds, has a pronounced analgesic activity in a wide range of doses of 0.0001–10 mg/kg.

Orofacial pain conditions are often very debilitating to the patient and difficult to treat. While clinical interest is high, the proportion of studies performed in the orofacial region in laboratory animals is relatively low, compared with other body regions. This is partly due to difficulties in testing freely moving animals and therefore lack of reliable testing methods. Here we present a comprehensive review of the currently used rodent models of inflammatory and neuropathic pain adapted to the orofacial areas, taking into account the difficulties and drawbacks of the existing approaches. We examine the available testing methods and procedures used for assessing the behavioral responses in the face in both mice and rats and provide a summary of some pharmacological agents used in these paradigms to date. The use of these agents in animal models is also compared with outcomes observed in the clinic.

Recent evidence suggests a role of transient receptor potential melastatin 2 (TRPM2) in immune and inflammatory responses. We previously reported that TRPM2 deficiency attenuated inflammatory and neuropathic pain in some pain mouse models, including formalin- or carrageenan-induced inflammatory pain, and peripheral nerve injury-induced neuropathic pain models, while it had no effect on the basal mechanical and thermal nociceptive sensitivities. In this study, we further explored the involvement of TRPM2 in various pain models using TRPM2-knockout mice. There were no differences in the chemonociceptive behaviors evoked by intraplantar injection of capsaicin or hydrogen peroxide between wildtype and TRPM2-knockout mice, while acetic acid-induced writhing behavior was significantly attenuated in TRPM2-knockout mice. In the postoperative incisional pain model, no difference in mechanical allodynia was observed between the two genotypes. By contrast, mechanical allodynia in the monosodium iodoacetate-induced osteoarthritis pain model and the experimental autoimmune encephalomyelitis model were significantly attenuated in TRPM2-knockout mice. Furthermore, mechanical allodynia in paclitaxel-induced peripheral neuropathy and streptozotocin-induced painful diabetic neuropathy models were significantly attenuated in TRPM2-knockout mice. Taken together, these results suggest that TRPM2 plays roles in a wide range of pathological pain models based on peripheral and central neuroinflammation, rather than physiological nociceptive pain.

Cannabinoid CB(2) receptor activation by selective agonists has been shown to produce analgesic effects in preclinical models of inflammatory, neuropathic, and bone cancer pain. In this study the effect of a novel CB(2)agonist (MT178) was evaluated in different animal models of pain. First of all, in vitro competition binding experiments performed on rat, mouse, or human CB receptors revealed a high affinity, selectivity, and potency of MT178. The analgesic properties of the novel CB(2) agonist were evaluated in various in vivo experiments, such as writhing and formalin assays, showing a good efficacy comparable with that produced by the nonselective CB agonist WIN 55,212-2. A dose-dependent antiallodynic effect of the novel CB(2) compound in the streptozotocin-induced diabetic neuropathy was found. In a bone cancer pain model and in the acid-induced muscle pain model, MT178 was able to significantly reduce mechanical hyperalgesia in a dose-related manner. Notably, MT178 failed to provoke locomotor disturbance and catalepsy, which were observed following the administration of WIN 55,212-2. CB(2) receptor mechanism of action was investigated in dorsal root ganglia where MT178 mediated a reduction of [(3)H]-d-aspartate release. MT178 was also able to inhibit capsaicin-induced substance P release and NF-κB activation. These results demonstrate that systemic administration of MT178 produced a robust analgesia in different pain models via CB(2) receptors, providing an interesting approach to analgesic therapy in inflammatory and chronic pain without CB(1)-mediated central side effects.

Sumithra Krishnan1, Amy Salter2, Thomas Sullivan2, Melanie Gentgall3, Jason White4, Paul Rolan11Discipline of Pharmacology, School of Medical Sciences, The University of Adelaide, 2Discipline of Public Health, The University of Adelaide, 3Pain and Anesthesia Research Clinic, Royal Adelaide Hospital, 4Pharmacy School, University of South Australia, Adelaide, South Australia, AustraliaObjective: Chronic opioid therapy may be associated with hyperalgesia. Our objective was to determine if opioid-induced hyperalgesia detection sensitivity is dependent on the stimulus used to detect it.Methods: This open design study compared the detection of hyperalgesia in opioid-dependent subjects (n = 16) and healthy control subjects (n = 16) using the following pain stimuli: cold pain, electrical stimulation, mechanical pressure, and ischemic pain. The opioid-dependent subjects were maintained on either methadone (n = 8) or buprenorphine (n = 8) for at least 3 months. None of the controls was dependent on opioids or other drugs of abuse.Results: The opioid-dependent subjects were markedly more sensitive than controls to the cold pain test. Compared with the control group, the hazard ratio for ceasing the test due to intolerable pain was 7.7 (95% confidence interval [CI] 2.6–23.3) in the buprenorphine group and 4.5 (95% CI 1.7–15.6) in the methadone group, with similar data for the cold pain threshold. Of the remaining tests, there were differences only for the electrical pain threshold between treatment groups, with the geometric mean threshold in the buprenorphine group being 1.5 (95% CI 1.1–1.9)-fold higher (ie, less sensitive) than that of the controls; the geometric mean for the methadone group was 1.3 (95% CI 1.04–1.7)-fold higher than that of the controls. There were no significant differences between buprenorphine and methadone patients in test responses. Women were more sensitive to the cold pain (hazard ratio for tolerance, 3.1 [95% CI 1.4–7.3]) and ischemic tests (hazard ratio for tolerance, 2.7 [95% CI 1.2–6.1]). There were significant correlations between cold and ischemic tolerances (r = 0.50; P = 0.003) and between electrical and mechanical pain tolerances (r = 0.52; P = 0.002).Conclusion: These findings indicate that cold pain is the most suitable of the methods tested to detect opioid-induced hyperalgesia. This is consistent with its sensitivity to detect opioid analgesia.Keywords: opioid-induced hyperalgesia, opioid-dependent subjects, pain models

We sought an optimal method for targeted delivery into dorsal root ganglia (DRGs) for experimental studies, in terms of precision of delivery and avoidance of behavioral disturbances. We examined three approaches for injection into rat DRGs: percutaneous injection without surgical exposure, injection after deep exposure, and injection following deep exposure and partial laminectomy. Coomassie blue and Fast Blue were injected into DRGs for validation. At necropsy, the spread of Coomassie blue and Fast Blue was investigated under stereomicroscope and fluorescent microscope, respectively. We found that percutaneous approach did not provide any successful DRG injections. Deep exposure prior to intraganglionic injection provided variable results, but intraganglionic injection after deep exposure plus partial laminectomy was successful in 100% of attempts. Our subsequent skeletal analysis showed that the anatomical location of DRG is not compatible with successful DRG injection without surgical exposure. Neither of the methods using surgical exposure caused behavioral disturbances. Based on these results we conclude that partial laminectomy offers the most precise method of injecting DRG and does not produce behavioral evidence of nerve damage. Intraganglionic injection after deep exposure alone is less predictable, while percutaneous approaches only allow injection in the peripheral nerve.

The experience of pain is variable among certain cultures, ethnical groups and among individuals. This variability can be explained by environmental influence, genetic predisposition and plasticity of the existing neuronal pathways. The purpose of this study was to examine a strain-related difference in pain sensitivity between Wistar and Sprague-Dawley rats strains and if there was a difference, could it be overcomes with the robust test. Mechanical sensitivity e.g. existence of paw withdrawal and complex hyperalgesia-type response after needle stimuli has been measured. Both hindpaws (middle, medial and lateral part) were stimulated randomly in appropriate intervals. The results did not demonstrate statistically significant strain difference in pain sensitivity, except in the lateral part of the hindpaw where Sprague-Dawley rats were more sensitive. This data emphasize the importance of selecting a robust behavior test that will be used in investigation of peripheral nerve injury and in neuropathic pain research.