Articles: hyperalgesia.
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Peripheral tissue injury results in a change in the excitability of spinal dorsal horn neurons, central sensitization, and the behavioral correlate, hyperalgesia. It is proposed here that a dynamic balance exists between excitatory and inhibitory synaptic input to the spinal dorsal horn that functions to prevent central sensitization following brief, mild, noxious stimulation. Following more severe stimulation and injury, there is a loss of these inhibitory mechanisms that allow central sensitization to proceed. ⋯ It is suggested that this attenuation, whether or not expressed, prevents a significant portion of deep dorsal horn neurons from becoming sensitized to C-fiber input. This functions to prevent central sensitization when the noxious stimulus does not produce inflammation and it is not beneficial to the animal to become hyperalgesic (i.e., to alter its behavior in order to protect an injured limb and reduce painful sensations). Following injury-producing tissue damage and inflammation the mechanisms that produce the attenuation are reduced, with a concomitant increase in excitation to electrical and natural stimuli, suggesting that the attenuation is inhibitory modulation of nociceptive input and injury results in a disinhibition producing an increase in excitability and central sensitization.
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To elucidate the involvement of nitric oxide in spinal nociceptive processing, the correlation of thermal withdrawal latency with nitric oxide synthase-stained neurons in the rat lumbar dorsal horn was analyzed after adjuvant-induced inflammation. From 4 hr through 5 days after subcutaneous injection of complete Freund's adjuvant into the hind paw, a marked thermal hyperalgesia was observed for heat stimulus applied to the affected region. NADPH-diaphorase- and nitric oxide synthase-positive neurons increased significantly in the superficial layers of the dorsal horn ipsilateral to the inflamed hind paw at day 3 of adjuvant-induced inflammation. ⋯ The intravenous administration of N omega-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg), an inhibitor of nitric oxide synthase, significantly blocked the adjuvant-induced thermal hyperalgesia at day 3 of inflammation, but not at day 1; and it had no effect in non-inflamed rats. This anti-hyperalgesic effect of L-NAME at day 3 of inflammation was reversed by the prior administration of L-arginine (600 mg/kg, i.p.), a substrate of nitric oxide synthase. These data suggest that nitric oxide producing neurons in the spinal dorsal horn are involved in maintaining and facilitating the hyperalgesia associated with chronic nociception.
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Neuroscience letters · Nov 1997
Formalin injection in the tail facilitates hindpaw withdrawal reflexes induced by thermal stimulation in the rat: effect of paracetamol.
With the aim to develop a simple behavioural method for the study of hyperalgesic processes and for the evaluation of anti-hyperalgesic properties of analgesic drugs, the effect of the tail injection of formalin (10% formaldehyde intradermally) on hindpaw nociceptive thresholds to thermal stimulation was evaluated in the rat. The formalin injection in the tail induced a significant reduction of plantar test latencies. ⋯ However, this drug was unable to block hyperalgesia when already established. Our results suggest that this method could be used for the evaluation of analgesic drugs in an experimental setting representative of clinical pain.
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Randomized Controlled Trial Clinical Trial
Effect of systemic N-methyl-D-aspartate receptor antagonist (dextromethorphan) on primary and secondary hyperalgesia in humans.
Dextromethorphan is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist known to inhibit wind-up and central hyperexcitability of dorsal horn neurones. We studied 24 healthy, unmedicated male volunteers, aged 21-28 yr, in a randomized, double-blind, placebo-controlled, crossover study. Burn injuries were produced on the medial surface of the dominant calf with a 25 x 50 mm rectangular thermode. ⋯ Side effects were frequent but clinically acceptable. The effects of dextromethorphan were in agreement with experimental studies indicating that dextromethorphan is a NMDA receptor antagonist. The effects of dextromethorphan in the burn injury model were similar to those of ketamine and distinct from those of local anaesthetics and opioids.
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Nociceptin is a 17-amino acid peptide and acts as a potent endogenous agonist of the opioid receptor-like1 receptor. Nociceptin is reported to depress glutamatergic transmission and to block the spinal facilitation that is thought to be mediated by the N-methyl-D-aspartate (NMDA) receptor. In the present study, the authors investigated the effect of intrathecally administered nociceptin and NMDA antagonists on the level of thermal hyperalgesia after partial sciatic nerve injury in the rat. ⋯ Intrathecal injection of nociceptin attenuated the level of thermal hyperalgesia induced by partial sciatic nerve injury, and NMDA receptor-dependent spinal facilitation does not play an important role in maintaining thermal hyperalgesia in rats with partial sciatic nerve injury.