Articles: hyperalgesia.
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Although previous reports have suggested that P2Y1 receptors (P2Y1Rs) are involved in cutaneous nociceptive signaling, it remains unclear how P2Y1Rs contribute to peripheral sensitization. The current study was designed to delineate the role of peripheral P2Y1Rs in pain and to investigate potential linkages to mitogen-activated protein kinase (MAPK) in DRGs and Transient Receptor Potential Vanilloid 1 (TRPV1) expression in a rodent inflammatory pain model. Following injection of 2% carrageenan into the hind paw, expressions of P2Y1 and TRPV1 and the phosphorylation rates of both p38 MAPK and ERK but not JNK were increased and peaked at day 2 post-injection. ⋯ Furthermore, inhibition of p38 activation in the DRGs by SB203580 (a p38 inhibitor, i.t, D0 to D2) prevented the upregulation of TRPV1 and a single i.t injection of SB203580 reversed the established thermal hyperalgesia, but not mechanical allodynia. Lastly, to identify the mechanism of action of P2Y1Rs, we repeatedly injected the P2Y1 agonist, MRS2365 into the naïve rat's hind paw and observed a dose-dependent increase in TRPV1 expression and p38 MAPK phosphorylation. These data demonstrate a sequential role for P2Y1R, p38 MAPK and TRPV1 in inflammation-induced thermal hyperalgesia; thus, peripheral P2Y1Rs activation modulates p38 MAPK signaling and TRPV1 expression, which ultimately leads to the induction of thermal hyperalgesia.
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Central neuropathic pain (CNP) is a debilitating consequence of central nervous system damage for which current treatments are ineffective. To explore mechanisms underlying CNP, we developed a rat model involving T13/L1 dorsal root avulsion. The resultant dorsal horn damage creates bilateral below-level (L4-L6) mechanical allodynia. This allodynia, termed spinal neuropathic avulsion pain, occurs in the absence of confounding paralysis. To characterize this model, we undertook a series of studies aimed at defining whether spinal neuropathic avulsion pain could be reversed by any of 3 putative glial activation inhibitors, each with distinct mechanisms of action. Indeed, the phosphodiesterase inhibitor propentofylline, the macrophage migration inhibitory factor inhibitor ibudilast, and the toll-like receptor 4 antagonist (+)-naltrexone each reversed below-level allodynia bilaterally. Strikingly, none of these impacted spinal neuropathic avulsion pain upon first administration but required 1 to 2 weeks of daily administration before pain reversal was obtained. Given reversal of CNP by each of these glial modulatory agents, these results suggest that glia contribute to the maintenance of such pain and enduring release of macrophage migration inhibitory factor and endogenous agonists of toll-like receptor 4 is important for sustaining CNP. The markedly delayed efficacy of all 3 glial modulatory drugs may prove instructive for interpretation of apparent drug failures after shorter dosing regimens. ⋯ CNP that develops after trauma is often described by patients as severe and intolerable. Unfortunately, current treatments are not effective. This work suggests that using pharmacologic treatments that target glial cells could be an effective clinical treatment for CNP.
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Annals of neurology · Apr 2014
Botulinum toxin-A treatment reduces human mechanical pain sensitivity and mechanotransduction.
The mechanisms underlying the analgesic effects of botulinum toxin serotype A (BoNT-A) are not well understood. We have tested the hypothesis that BoNT-A can block nociceptor transduction. ⋯ In cultured rodent primary sensory neurons, BoNT-A decreased the proportion of neurons expressing slowly adapting mechanically gated currents linked to mechanical pain transduction. Inhibition of mechanotransduction provides a novel locus of action of BoNT-A, further understanding of which may extend its use as an analgesic agent.
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N-type calcium channels play important roles in the control of neurotransmission release and transmission of pain signals to the central nervous system. Their selective inhibitors are believed to be potential drugs for treating chronic pain. In this study, a novel neurotoxin named Huwentoxin-XVI (HWTX-XVI) specific for N-type calcium channels was purified and characterized from the venom of Chinese tarantula Ornithoctonus huwena. ⋯ Toxin treatment also changed withdrawal latency in hot plate tests. Intriguingly, we found that intramuscular injection of the toxin reduced mechanical allodynia induced by incisional injury in Von Frey test. Thus, our findings suggest that the analgesic potency of HWTX-XVI and its greater reversibility could contribute to the design of a novel potential analgesic agent with high potency and low side effects.
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Arthritis Rheumatol · Apr 2014
Activation of spinal NF-κB/p65 contributes to peripheral inflammation and hyperalgesia in rat adjuvant-induced arthritis.
It is known that noxious stimuli from inflamed tissue may increase the excitability of spinal dorsal horn neurons (a process known as central sensitization), which can signal back and contribute to peripheral inflammation. However, the underlying mechanisms have yet to be fully defined. A number of recent studies have indicated that spinal NF-κB/p65 is involved in central sensitization, as well as pain-related behavior. Thus, the aim of this study was to determine whether NF-κB/p65 can facilitate a peripheral inflammatory response in rat adjuvant-induced arthritis (AIA). ⋯ These findings indicate that spinal NF-κB/p65 plays an important role in the initiation and development of both peripheral inflammation and hyperalgesia. Thus, inhibition of spinal NF-κB/p65 expression may provide a potential treatment to manage painful inflammatory disorders.