Mol Pain
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Artemin (Artn), a member of the glial cell line-derived growth factor (GDNF) family, supports the development and function of a subpopulation of peptidergic, TRPV1-positive sensory neurons. Artn (enovin, neublastin) is elevated in inflamed tissue and its injection in skin causes transient thermal hyperalgesia. A genome wide expression analysis of trigeminal ganglia of mice that overexpress Artn in the skin (ART-OE mice) showed elevation in nicotinic acetylcholine receptor (nAChR) subunits, suggesting these ion channels contribute to Artn-induced sensitivity. Here we have used gene expression, immunolabeling, patch clamp electrophysiology and behavioral testing assays to investigate the link between Artn, nicotinic subunit expression and thermal hypersensitivity. ⋯ These findings suggest that Artn regulates the expression and composition of nAChRs in GFRα3 nociceptors and that these changes contribute to the thermal hypersensitivity that develops in response to Artn injection and perhaps to inflammation.
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T-type calcium channels and cannabinoid receptors are known to play important roles in chronic pain, making them attractive therapeutic targets. We recently reported on the design, synthesis and analgesic properties of a novel T-type channel inhibitor (NMP-7), which also shows mixed agonist activity on CB1 and CB2 receptors in vitro. Here, we analyzed the analgesic effect of systemically delivered NMP-7 (intraperitoneal (i.p.) or intragstric (i.g.) routes) on mechanical hypersensitivity in inflammatory pain induced by Complete Freund's Adjuvant (CFA) and neuropathic pain induced by sciatic nerve injury. ⋯ Overall, our work shows that NMP-7 mediates a significant analgesic effect in a model of persistent inflammatory and chronic neuropathic pain by way of T-type channel modulation and CB2 receptor activation. Thus, this study provides a novel therapeutic avenue for managing chronic pain conditions via mixed CB ligands/T-type channel blockers.
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Neuropathic pain is believed to be influenced in part by inflammatory processes. In this study we examined the effect of variability in the C-type lectin gene cluster (Aplec) on the development of neuropathic pain-like behavior after ligation of the L5 spinal nerve in the inbred DA and the congenic Aplec strains, which carries seven C-type lectin genes originating from the PVG strain. ⋯ We here for the first time demonstrate that C-type lectins, a family of innate immune receptors with largely unknown functions in the nervous system, are involved in regulation of inflammation and development of neuropathic pain behavior after nerve injury. Further experimental and clinical studies are needed to dissect the underlying mechanisms more in detail as well as any possible relevance for human conditions.
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Chemotherapeutic treatment results in chronic pain in an estimated 30-40 percent of patients. Limited and often ineffective treatments make the need for new therapeutics an urgent one. We compared the effects of prophylactic cannabinoids as a preventative strategy for suppressing development of paclitaxel-induced nociception. The mixed CB1/CB2 agonist WIN55,212-2 was compared with the cannabilactone CB2-selective agonist AM1710, administered subcutaneously (s.c.), via osmotic mini pumps before, during, and after paclitaxel treatment. Pharmacological specificity was assessed using CB1 (AM251) and CB2 (AM630) antagonists. The impact of chronic drug infusion on transcriptional regulation of mRNA markers of astrocytes (GFAP), microglia (CD11b) and cannabinoid receptors (CB1, CB2) was assessed in lumbar spinal cords of paclitaxel and vehicle-treated rats. ⋯ Cannabinoids block development of paclitaxel-induced neuropathy and protect against neuropathic allodynia following cessation of drug delivery. Chronic treatment with both mixed CB1/CB2 and CB2 selective cannabinoids increased mRNA expression of cannabinoid receptors (CB1, CB2) in a CB2-dependent fashion. Our results support the therapeutic potential of cannabinoids for suppressing chemotherapy-induced neuropathy in humans.
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It is well-documented that neonates can experience pain after injury. However, the contribution of individual populations of sensory neurons to neonatal pain is not clearly understood. Here we characterized the functional response properties and neurochemical phenotypes of single primary afferents after injection of carrageenan into the hairy hindpaw skin using a neonatal ex vivo recording preparation. ⋯ These data suggest that the mechanisms of neonatal pain development may be generated by different afferent subtypes and receptors/channels in an age-related manner.