Articles: hyperalgesia.
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Anesthesia and analgesia · Oct 2002
Hyperalgesia during opioid abstinence: mediation by glutamate and substance p.
Opioid-abstinence hyperalgesia (OAH) is a phenomenon characterized by thermal and mechanical hyperalgesia that occurs between intermittent doses of opioids or after the chronic administration of these drugs when administration is abruptly stopped. In these studies we attempted to determine whether the activation of spinal cord dorsal horn neurons was greater in mice with OAH than in control mice in response to the intrathecal administration of the primary neurotransmitters glutamate and substance P. After mice were treated with an established protocol consisting of the implantation of morphine pellets followed by removal after 6 days, the mice were hyperalgesic as assessed with the hotplate and Hargreaves thermal paw withdrawal assays. Mechanical allodynia was also demonstrated. The intrathecal injection of either glutamate (5-25 micro g) or substance P (0.02-0.1 nmol) caused greater pain behaviors in mice with OAH than in control mice. Likewise, it was observed that the dorsal horn regions of OAH mice had more Fos-positive nuclei after either glutamate or substance P administration than did control mice. We conclude that mice with OAH exhibit increased pain behaviors and have increased numbers of Fos-positive nuclei in response to intrathecal glutamate and substance P administration when compared with control mice. Thus, spinal sensitization to primary neurotransmitters may be responsible in part for the manifestation of OAH. ⋯ Opioids are a mainstay of treatment for many types of chronic pain. These studies provide evidence that the hyperalgesia induced by chronic opioid administration may be in part to spinal neuroplastic changes.
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Peripheral inflammation induces p38 MAPK activation in the soma of C fiber nociceptors in the dorsal root ganglion (DRG) after 24 hr. Inflammation also increases protein, but not mRNA levels, of the heat-gated ion channel TRPV1 (VR1) in these cells, which is then transported to peripheral but not central C fiber terminals. Inhibiting p38 activation in the DRG reduces the increase in TRPV1 in the DRG and inflamed skin and diminishes inflammation-induced heat hypersensitivity without affecting inflammatory swelling or basal pain sensitivity. p38 activation in the DRG is secondary to peripheral production of NGF during inflammation and is required for NGF-induced increases in TRPV1. The activation of p38 in the DRG following retrograde NGF transport, by increasing TRPV1 levels in nociceptor peripheral terminals in a transcription-independent fashion, contributes to the maintenance of inflammatory heat hypersensitivity.
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The excitation of nociceptive sensory neurons by ATP released in injured tissue is believed to be mediated partly by P2X3 receptors. Although an analysis of P2X3 knock-out mice has revealed some deficits in nociceptive signaling, detailed analysis of the role of these receptors is hampered by the lack of potent specific pharmacological tools. Here we have used antisense oligonucleotides (ASOs) to downregulate P2X3 receptors to examine their role in models of chronic pain in the rat. ⋯ In models of neuropathic (partial sciatic ligation) and inflammatory (complete Freund's adjuvant) pain, inhibition of the development of mechanical hyperalgesia as well as significant reversal of established hyperalgesia were observed within 2 d of ASO treatment. The time course of the reversal of hyperalgesia is consistent with downregulation of P2X3 receptor protein and function. This study demonstrates the utility of ASO approaches for validating gene targets in in vivo pain models and provides evidence for a role of P2X3 receptors in the pathophysiology of chronic pain.
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J. Pharmacol. Exp. Ther. · Sep 2002
Chronic muscle pain induced by repeated acid Injection is reversed by spinally administered mu- and delta-, but not kappa-, opioid receptor agonists.
Opioids are commonly used for pain relief clinically and reduce hyperalgesia in most animal models. Two injections of acidic saline into one gastrocnemius muscle 5 days apart produce a long-lasting bilateral hyperalgesia without associated tissue damage. The current study was undertaken to assess the effects of opioid agonists on mechanical hyperalgesia induced by repeated intramuscular injections of acid. ⋯ The reduction in hyperalgesia produced by morphine and DAMGO was prevented by H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) and that of SNC80 was prevented by naltrindole. U50,488 had no effect on the decreased mechanical withdrawal thresholds. Thus, activation of mu- and delta-, but not kappa-, opioid receptors in the spinal cord reduces mechanical hyperalgesia following repeated intramuscular injection of acid, thus validating the use of this new model of chronic muscle pain.
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Randomized Controlled Trial Clinical Trial
Different mechanisms of development and maintenance of experimental incision-induced hyperalgesia in human skin.
To determine the mechanisms of postoperative pain, the effects of local anesthesia on development and maintenance of surgical incision-induced hyperalgesia were evaluated in a crossover, double-blinded, placebo-controlled human study using 17 subjects. ⋯ Pretraumatic injection of lidocaine reduces primary hyperalgesia more effectively than does posttraumatic injection, but only for a short period after incision. The spread of secondary hyperalgesia is mediated peripheral nerve fibers, but when secondary hyperalgesia has fully developed, it becomes less dependent on or even independent of peripheral neural activity originating from the injured site.