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Chronic pain is a frequent, distressing and poorly understood health problem. Plasticity of synaptic transmission in the nociceptive pathways after inflammation or injury is assumed to be an important cellular basis for chronic, pathological pain. Glutamate serves as the main excitatory neurotransmitter at key synapses in the somatosensory nociceptive pathways, in which it acts on both ionotropic and metabotropic glutamate receptors. Although conventionally postsynaptic, compelling anatomical and physiological evidence demonstrates the presence of presynaptic glutamate receptors in the nociceptive pathways. Presynaptic glutamate receptors play crucial roles in nociceptive synaptic transmission and plasticity. They modulate presynaptic neurotransmitter release and synaptic plasticity, which in turn regulates pain sensitization. In this review, we summarize the latest understanding of the expression of presynaptic glutamate receptors in the nociceptive pathways, and how they contribute to nociceptive information processing and pain hypersensitivity associated with inflammation / injury. We uncover the cellular and molecular mechanisms of presynaptic glutamate receptors in shaping synaptic transmission and plasticity to mediate pain chronicity, which may provide therapeutic approaches for treatment of chronic pain. [ABSTRACT FROM AUTHOR]

Background & Aims: The neurobiologic basis of pancreatic hyperalgesia in chronic pancreatitis (CP) is understood poorly and there is a need to identify novel therapeutic targets. Our aim was to study the role of the transient receptor potential vanilloid 1 (TRPV1), a key integrator of noxious stimuli, in the pathogenesis of pancreatic pain in a rat model of CP. Methods: CP was induced in rats by intraductal injection of trinitrobenzene sulfonic acid. TRPV1 currents in pancreas-specific DRG neurons were measured using perforated patch-clamp techniques. Reverse-transcription polymerase chain reaction was used to measure mRNA expression of TRPV1 in these neurons after laser capture microdissection. Immunofluorescence and Western blot analysis, using TRPV1-specific antibodies, also were performed. Pancreatic hyperalgesia was assessed by rat’s nocifensive behavior to electrical stimulation of the pancreas. Results: CP was associated with a 4-fold increase in capsaicin-induced current density (P < .02), along with an increase in the proportion of pancreas-specific DRG neurons that responded to capsaicin (52.9% in controls vs 79.0% in CP; P < .05). CP also was associated with a significant increase in TRPV1 expression both at the messenger RNA and protein level in whole thoracic DRGs and pancreas-specific sensory neurons. Systemic administration of the TRPV1 antagonist SB-366791 markedly reduced both visceral pain behavior and referred somatic hyperalgesia in rats with CP, but not in control animals. Conclusions: TRPV1 up-regulation and sensitization is a specific molecular mechanism contributing to hyperalgesia in CP and represents a useful target for treating pancreatic hyperalgesia caused by inflammation. [Copyright &y& Elsevier]

Primary afferent neurons in mammalian dorsal root ganglia (DRGs) normally function as independent sensory communication elements. However, it has recently been shown that most DRG neurons are transiently activated when axons of neighboring neurons of the same ganglion are stimulated repetitively and the cross-depolarization contributes to this mutual cross-excitation. Here, we reported the cross-inhibition of mechanoreceptive information in DRG under peripheral inflammatory condition. Intracellular recordings were made in vivo from A-type afferent neurons in cat L6–7 DRGs. Among spontaneously firing neurons both from control (Con) and carrageenan (Carg) injected cats, some A-type afferent neurons showed to have two distinct receptive fields on the hindpaw. Mechanical stimulation of one receptive field increased the ongoing activities, while stimulation of the other receptive field led to a decrease of spontaneous firings of the same neuron. These two distinct receptive fields are termed excitatory receptive field (ERF) and inhibitory receptive field (IRF), respectively. Peripheral inflammation significantly increased the prevalence of Aβ and Aδ neurons with two distinct receptive fields (Aβ: Con, 1.34%, n=149; Carg, 6.59%, n=182; P<0.05; Aδ: Con, 0%, n=138, Carg, 3.9%, n=102, P<0.05). Most interestedly, ERF stimulation-induced enhancement of cell firings can be suppressed by IRF stimulation. Similarly, IRF stimulation-induced decrease of cell discharges can be reversed by ERF stimulation. This interaction was not affected by cutting the dorsal roots at the place close to the recorded DRG. Preapplication of naloxone and yohimbine did not block the interaction. Taken together with previous reports, this intraganglionic cross-talking appears to be mediated by collision of retrograde spread of action potentials, or/and at least in part, by an activity-dependent diffusible excitatory substance released from neuronal somata and/or adjacent axons, and detected by neighboring cell somata. [Copyright &y& Elsevier]

Background & Aims: Chronic stress exacerbates or causes relapse of symptoms such as abdominal pain and cramping in patients with irritable bowel syndrome. We investigated whether chronic stress increases plasma norepinephrine and sensitizes colon-specific dorsal root ganglion (DRG) neurons by increasing expression of nerve growth factor (NGF) in the colon wall. Methods: Heterotypic chronic stress (HeCS) was applied to male Wistar rats and neurologic and molecular responses were analyzed. Tissues were analyzed for NGF expression. Results: HeCS significantly increased visceromoter response to colorectal distension; expression of NGF increased in colonic muscularis externa and mucosa/submucosa. Rheobase decreased, resting membrane potential was depolarized, and electrogenesis of action potentials increased in colon-specific thoracolumbar DRG neurons. Luminal administration of resiniferatoxin in distal colon, systemic administration of anti-NGF antibody, or inhibition of the NGF receptor trkA by k252a or antisense oligonucleotides in thoracolumbar DRG blocked the chronic stress-induced visceral hypersensitivity to colorectal distension. Blockade of α1/α2- and β1/β2-adrenergic receptors prevented the stress-induced visceral hypersensitivity and increased expression of NGF in the colon wall. HeCS did not induce any inflammatory response in the colon wall. Conclusions: The peripheral stress mediator norepinephrine induces visceral hypersensitivity to colorectal distension in response to HeCS by increasing the expression of NGF in the colon wall, which sensitizes primary afferents in the absence of an inflammatory response. [Copyright &y& Elsevier]

Highlights • Behavioral analysis demonstrated that the CPSP animals displayed a significant decrease in mechanical allodynia threshold. • A significant increase in P2 × 4 receptors expression in microglia in thalamic peri-lesion tissues post-hemorrhage. • The mechanical allodynia in rats with CPSP were reversed by blocking P2 × 4 receptors. • A significant alleviation of mechanical allodynia was achieved following the administration of adrenergic antidepressants and antiepileptics. • A significant decrease in P2 × 4 receptor expression after treatment with adrenergic antidepressants and antiepileptics. Abstract Stroke is the leading cause of disability and death in the world. Central post-stroke pain (CPSP), a central neuropathic pain syndrome occurring after cerebral stroke, is a serious problem. But on account of the lack of reliable animal models, the mechanisms underlying CPSP remains poorly understood. To better understand of the pathophysiological basis of CPSP, we developed and characterized a new rat model of CPSP. This model is based on a hemorrhagic stroke lesion with intra-thalamic autologous blood (ITAB) injection in the ventral posterolateral nucleus of the thalamus. Behavioral analysis demonstrated that the animals displayed a significant decrease in mechanical allodynia threshold. We found a significant increase in P2 × 4 receptor expression in microglia in thalamic peri-lesion tissues post-hemorrhage. The mechanical allodynia in rats with CPSP were reversed by blocking P2 × 4 receptors. A significant alleviation of mechanical allodynia was achieved following the administration of adrenergic antidepressants and antiepileptics. Meanwhile, we found a significant decrease in P2 × 4 receptor expression after treatment with these drugs. Taken together, our results suggest that targeting P2 × 4 receptor may be effective in the treatment of CPSP. [ABSTRACT FROM AUTHOR]

Aims Accumulating evidence supports that cerebrospinal fluid (CSF) in the subarachnoid space (SAS) could reenter the brain parenchyma via the glymphatic influx. The present study was designed to characterize the detailed pathway of subarachnoid CSF influx by using a novel CSF tracer. Main methods Fluorescently conjugated cadaverine (A488-ca), for the first time, was employed to investigate CSF movement in the brain. Following intracisternal infusion of CSF tracers, mice brain was sliced and prepared for fluorescence imaging. Some brain sections were immunostained in order to observe tracer distribution and cellular uptake. Key findings A488-ca moved into the brain parenchyma rapidly, and the influx was time and region dependent. A488-ca entered the mice brain more readily and spread more widely than another commonly used CSF tracer-fluorescently conjugated ovalbumin (OA-45). Furthermore, A488-ca could enter the brain parenchyma either along the paravascular space or across the pial surface. Suppression of glymphatic transport by administration with acetazolamide strikingly reduced the influx of A488-ca. More importantly, relative to OA-45 largely remained in the extracellular space, A488-ca exhibited obvious cellular uptake by astrocytes surrounding the blood vessels and neurons in the cerebral cortex. Significance Subarachnoid CSF could flow into the brain parenchyma via the glymphatic influx, in which the transcellular pathway was faithfully traced by intracisternal infusion with fluorescently conjugated cadaverine. These observations extend our comprehension on the glymphatic influx pathway. [ABSTRACT FROM AUTHOR]

[Display omitted] • Metformin obviously attenuates mechanical allodynia of diabetic rats. • Activation of AMPK contributes to analgesic effect of Metformin on diabetic rats. • Activation of AMPK decreased the expression of NF-κB in diabetic rats. Neuropathic pain is a common complication of diabetes mellitus with poorly relieved by conventional analgesics. Metformin, a first-line drug for type 2 diabetes, reduces blood glucose by activating adenosine monophosphate protein kinase (AMPK) signalling system. However, the effect of Metformin on diabetic neuropathic pain is still unknown. In the present study, we showed that Metformin was capable of attenuating diabetes induced mechanical allodynia, and the analgesia effect could be blocked by Compound C (an AMPK inhibitor). Importantly, Metformin enhanced the phosphorylation level of AMPK in L4-6 DRGs of diabetic rats but not affect the expression of total AMPK. Intrathecal injection of AICAR (an AMPK agonist) could activate AMPK and alleviate the mechanical allodynia of diabetic rats. Additionally, phosphorylated AMPK and NF-κB was co-localized in small and medium neurons of L4-6 DRGs. Interestingly, the regulation of NF-κB in diabetic rats was obviously reduced when AMPK was activated by AICAR. Notably, Metformin could decrease NF-κB expression in L4-6 DRGs of diabetic rats, but the decrease was blocked by Compound C. In conclusion, Metformin alleviates diabetic mechanical allodynia via activation of AMPK signaling pathway in L4-6 DRGs of diabetic rats, which might be mediated by the downregulation of NF-κB, and this providing certain basis for Metformin to become a potential drug in the clinical treatment of diabetic neuropathic pain. [ABSTRACT FROM AUTHOR]