Articles: hyperalgesia.
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Anesthesia and analgesia · Sep 1998
Randomized Controlled Trial Clinical TrialIntrathecal, but not intravenous, clonidine reduces experimental thermal or capsaicin-induced pain and hyperalgesia in normal volunteers.
Clonidine is approved for intraspinal administration in the treatment of neuropathic cancer pain. Some studies have suggested an analgesic effect after systemic clonidine administration. The purpose of this study was to compare the analgesic effects of intrathecal and IV clonidine with acute noxious stimulation and with hyperalgesia from intradermal capsaicin injection in volunteers. Sixteen healthy volunteers received intradermal injections of capsaicin (100 microg) before and after the IV or intrathecal injection of clonidine 50 or 150 microg in a randomized, double-blind manner. Pain and areas of mechanical hyperalgesia and allodynia were determined at specified intervals. In addition, pain to noxious heat stimulation was determined. The capsaicin injection produced pain, followed by hyperalgesia and allodynia. The intrathecal, but not IV, injection of 150 microg of clonidine reduced capsaicin-induced pain and area of hyperalgesia. Intrathecal clonidine (150 microg) reduced pain to heat stimulation, whereas IV clonidine did not. The groups did not differ in hemodynamic or sedative effects from clonidine. These data support the value of intraspinal administration of clonidine for the treatment of acute pain and of pain states associated with hyperalgesia. Similarly, they suggest that analgesia from the systemic administration of this alpha2-adrenergic agonist, if any, is weak in doses that produce sedation and reduce blood pressure. ⋯ To the extent that the experimental pain conditions used in this study reflect those in patients with acute and chronic pain, these data support the spinal rather than IV injection of clonidine for analgesia.
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We investigated the role of nitric oxide (NO) in inflammatory hyperalgesia. Coinjection of prostaglandin E2 (PGE2) with the nitric oxide synthase (NOS) inhibitor NG-methyl-L-arginine (L-NMA) inhibited PGE2-induced hyperalgesia. L-NMA was also able to reverse that hyperalgesia. ⋯ Consistent with the hypothesis that these mechanisms are distinct, we found that inhibition of PGE2-induced hyperalgesia caused by L-NMA could be reversed by a low dose of the NO donor SIN-1. The following facts suggest that this dose of SIN-1 mimics a permissive effect of basal levels of NO with regard to PGE2-induced hyperalgesia: (1) this dose of SIN-1 does not produce hyperalgesia when administered alone, and (2) the effect was not blocked by ODQ. In conclusion, we have shown that low levels of NO facilitate cAMP-dependent PGE2-induced hyperalgesia, whereas higher levels of NO produce a cGMP-dependent hyperalgesia.
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The effect of neuropeptide FF in the periaqueductal gray on pain behaviour was studied in rats with a chronic neuropathy induced by unilateral ligation of two spinal nerves. Neuropeptide FF produced in a non-monotonic fashion a significant attenuation of tactile allodynia. The antiallodynic effect was not significantly modulated by naloxone administered systemically or intracerebrally. ⋯ The results indicate that neuropeptide FF in the periaqueductal gray may produce a selective attenuation of tactile allodynia in neuropathic rats. This antiallodynic effect is at least partly independent of naloxone-sensitive opioid receptors. Furthermore, neuropeptide FF in the periaqueductal gray attenuates antinociception induced by intracerebrally but not systemically administered morphine.
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The mechanisms by which nerve growth factor (NGF) induces thermal hyperalgesia and neutrophil accumulation have been investigated in the rat. Thermal nociceptive thresholds in rat hind paw were measured as the time taken for paw withdrawal from a heat source and neutrophil accumulation was measured in hind paw and dorsal skin samples using a myeloperoxidase assay. NGF (23-80 pmol intraplantar (i.pl.) injection) induced a significant (P < 0.05, n = 6-16) thermal hyperalgesia at 5 h after injection and significant neutrophil accumulation (P < 0.05, n = 6) was observed with NGF (40 pmol). ⋯ The 5-lipoxygenase inhibitor ZM230487 (10 nmol co-injected with NGF) significantly attenuated neutrophil accumulation and hyperalgesia induced by NGF; unlike the histamine and 5-hydroxytryptamine antagonists (mepyramine and methysergide) which were without effect at the times measured. Furthermore, depletion of circulating neutrophils (using a rabbit anti-rat neutrophil antibody) abolished NGF induced hyperalgesia. These results indicate that neutrophils, which accumulate in response to a 5-lipoxygenase product, play a crucial role in NGF-induced hyperalgesia.
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Recent studies suggest that calcium contributes to peripheral neural mechanisms of hyperalgesia associated with nerve damage. In this animal behavioural study, we examined further the contribution of calcium in neuropathic pain by testing whether subcutaneous administration of either a calcium chelating agent or voltage-dependent calcium channel blockers attenuate nerve injury-induced hyperalgesia to mechanical stimulation. Studies were carried out in animals with partially ligated sciatic nerves, an established animal model of neuropathic pain. ⋯ In control experiments, SNX-111 had no effect on mechanical thresholds when administered subcutaneously in either the hindpaw of normal animals or the back of the neck in nerve injury animals. This study shows that neuropathic pain involves a local calcium-dependent mechanism in the receptive field of intact neurons of an injured nerve, since it can be alleviated by subcutaneous injections of either a calcium chelating agent or SNX-111, a N-type calcium channel blocker. These agents may be effective, peripherally acting therapeutic agents for neuropathic pain.