Articles: hyperalgesia.
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P2Y2 is a member of the P2Y family of G protein-coupled nucleotide receptors that is widely co-expressed with TRPV1 in peripheral sensory neurons of the dorsal root ganglia. To characterize P2Y2 function in cutaneous afferents, intracellular recordings from mouse sensory neurons were made using an ex vivo preparation in which hindlimb skin, saphenous nerve, dorsal root ganglia and spinal cord are dissected intact. The peripheral response properties of individual cutaneous C-fibers were analyzed using digitally controlled mechanical and thermal stimuli in male P2Y2(+/+) and P2Y2(-/-) mice. ⋯ However, we also identified an atypical population of IB4-negative, TRPV1-positive CMH fibers. Compared to wildtype CMH fibers, these TRPV1-positive neurons exhibited lower firing rates in response to mechanical stimulation, but had increased firing to noxious heat (43-51°C). Collectively, these results demonstrate that P2Y2 contributes to response properties of cutaneous afferents, as P2Y2 deletion reduces responsiveness of conventional unmyelinated polymodal afferents to heat and appears to result in the acquisition of mechanical responsiveness in a subset of TRPV1-expressing afferents.
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Spinal plasticity, a key process mediating neuropathic pain development, requires ubiquitination-dependent protein turnover. Presynaptic active zone proteins have a crucial role in regulating vesicle exocytosis, which is essential for synaptic plasticity. Nevertheless, the mechanism for ubiquitination-regulated turnover of presynaptic active zone proteins in the progression of spinal plasticity-associated neuropathic pain remains unclear. Here, after research involving Sprague Dawley rats, we reported that spinal nerve ligation (SNL), in addition to causing allodynia, enhances the Rab3-interactive molecule-1α (RIM1α), a major active zone protein presumed to regulate neural plasticity, specifically in the synaptic plasma membranes (SPMs) of the ipsilateral dorsal horn. Spinal RIM1α-associated allodynia was mediated by Fbxo3, which abates Fbxl2-dependent RIM1α ubiquitination. Subsequently, following deubiquitination, enhanced RIM1α directly binds to CaV2.2, resulting in increased CaV2.2 expression in the SPMs of the dorsal horn. While exhibiting no effect on Fbxo3/Fbxl2 signaling, the focal knockdown of spinal RIM1α expression reversed the SNL-induced allodynia and increased spontaneous EPSC (sEPSC) frequency by suppressing RIM1α-facilitated CaV2.2 expression in the dorsal horn. Intrathecal applications of BC-1215 (a Fbxo3 activity inhibitor), Fbxl2 mRNA-targeting small-interfering RNA, and ω-conotoxin GVIA (a CaV2.2 blocker) attenuated RIM1α upregulation, enhanced RIM1α expression, and exhibited no effect on RIM1α expression, respectively. These results confirm the prediction that spinal presynaptic Fbxo3-dependent Fbxl2 ubiquitination promotes the subsequent RIM1α/CaV2.2 cascade in SNL-induced neuropathic pain. Our findings identify a role of the presynaptic active zone protein in pain-associated plasticity. That is, RIM1α-facilitated CaV2.2 expression plays a role in the downstream signaling of Fbxo3-dependent Fbxl2 ubiquitination/degradation to promote spinal plasticity underlying the progression of nociceptive hypersensitivity following neuropathic injury. ⋯ Ubiquitination is a well known process required for protein degradation. Studies investigating pain pathology have demonstrated that ubiquitination contributes to chronic pain by regulating the turnover of synaptic proteins. Here, we found that the spinal presynaptic active zone protein Rab3-interactive molecule-1α (RIM1α) participates in neuropathic pain development by binding to and upregulating the expression of CaV2.2. In addition, Fbxo3 modifies this pathway by inhibiting Fbxl2-mediated RIM1α ubiquitination, suggesting that presynaptic protein ubiquitination makes a crucial contribution to the development of neuropathic pain. Research in this area, now in its infancy, could potentially provide a novel therapeutic strategy for pain relief.
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Recent studies indicated the involvement of some chemokines in the development of diabetic neuropathy; however, participation of the chemokine-C-motif ligand (XCL) subfamily remains unknown. The goal of this study was to examine how microglial inhibition by minocycline hydrochloride (MC) influences chemokine-C-motif ligand 1 (XCL1)-chemokine-C-motif receptor 1 (XCR1)/G protein-coupled receptor 5 expression and the development of allodynia/hyperalgesia in streptozotocin-induced diabetic neuropathy. ⋯ In diabetic neuropathy, declining levels of XCL1 evoked by microglia inhibition result in the cause of analgesia. The putative mechanism corroborating this finding can be related to lower spinal expression of XCR1 together with the lack of stimulation of these XCR1 receptors, which are localized on neurons.
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J. Pharmacol. Exp. Ther. · Sep 2016
Selective Cathepsin S Inhibition with MIV-247 Attenuates Mechanical Allodynia and Enhances the Antiallodynic Effects of Gabapentin and Pregabalin in a Mouse Model of Neuropathic Pain.
Cathepsin S inhibitors attenuate mechanical allodynia in preclinical neuropathic pain models. The current study evaluated the effects when combining the selective cathepsin S inhibitor MIV-247 with gabapentin or pregabalin in a mouse model of neuropathic pain. Mice were rendered neuropathic by partial sciatic nerve ligation. ⋯ A subeffective dose of MIV-247 (50 µmol/kg) in combination with a subeffective dose of pregabalin (38 µmol/kg) or gabapentin (73 µmol/kg) also resulted in substantial efficacy. Plasma levels of MIV-247, gabapentin, and pregabalin were similar when given in combination as to when given alone. Cathepsin S inhibition with MIV-247 exerts significant antiallodynic efficacy alone, and also enhances the effect of gabapentin and pregabalin without increasing side effects or inducing pharmacokinetic interactions.
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Review
Progress of clinical practice on the management of burn-associated pain: Lessons from animal models.
Opioid-based analgesics provide the mainstay for attenuating burn pain, but they have a myriad of side effects including respiratory depression, nausea, impaired gastrointestinal motility, sedation, dependence, physiologic tolerance, and opioid-induced hyperalgesia. To test and develop novel analgesics, validated burn-relevant animal models of pain are indispensable. Herein we review such animal models, which are mostly limited to rodent models of burn-induced, inflammatory, and neuropathic pain. ⋯ Moreover, common clinical concerns such as systemic inflammatory response syndrome and multiple organ dysfunction remain unaddressed. For development of analgesics, these aberrations can significantly alter the potential efficacy and/or adverse effects of a prescribed analgesic following burn trauma. We therefore suggest that a multi-model strategy would be the most clinically relevant when evaluating novel analgesics for use in burn patients.