Articles: hyperalgesia.
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Previous work demonstrated that, in rats, intrathecal GR89696, a putative kappa-2 opioid receptor agonist, inhibited hyperalgesia to noxious heat in an inflamed hind paw (anti-hyperalgesic effect). Non-inflamed paws were not influenced by kappa-2 receptor activation. The question addressed in this study was whether GR89696 was as effective in blocking hyperalgesia and allodynia in nerve injury models as it was in the inflammation model. ⋯ Naloxone (1 mg/kg, i.p.) reversed the anti-hyperalgesic and anti-allodynic effects of GR89696. The mu agonist DAMGO (6 nmoles, i.t.) and the kappa-1 agonist U69593 (100 nmoles, i.t.) only partially reversed hyperalgesia and allodynia. These findings suggest that kappa-2 opioid receptors may be a useful target for the pharmacological control of hyperalgesia and allodynia.
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The L5 spinal nerve ligation model of neuropathic pain in rats has been proposed as a model for sympathetically maintained pain (SMP) based on the effects of surgical or chemical sympathectomy on nerve injury induced behavior. In an attempt to confirm that the lesion produces an animal model of SMP, surgical sympathectomies were independently conducted in two different laboratories (Johns Hopkins and University Kiel) using male Sprague-Dawley (n = 30) or Wistar rats (n = 14). The L5 spinal nerve was ligated or cut and ligated. ⋯ Experiments in Wistar and Sprague-Dawley rats yielded the same results. Potential reasons for the discrepancies between the present study and earlier reports are discussed. These results indicate that an L5 spinal nerve injury rat model is not a reliable model for SMP.
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The development of alpha-adrenergic sensitivity in cutaneous nociceptors has been postulated as a mechanism for sympathetically maintained pain (SMP). In order to characterize the adrenergic receptors involved, we investigated the effects of intraplantar administration of alpha1-(prazosin) and alpha2-(yohimbine) adrenergic antagonists and systemic injection of phentolamine, a non-specific alpha-adrenergic blocker, on allodynic/hyperalgesic behavior in an animal model thought to mimic SMP in humans. Peripheral neuropathy in rats was induced by tight ligation of the L5/L6 spinal nerves. ⋯ Intradermal administration of yohimbine or prazosin did not significantly alleviate mechanical hyperalgesia in L5/L6 ligated animals. Also systemic administration of phentolamine (1 and 5 mg/kg) did not alleviate the increased incidence of paw withdrawal in L5/L6 spinal nerve ligated animals. These results suggest that an alpha adrenergic interaction between sympathetic efferent and somatic afferent fibers does not play a critical role for the maintenance of mechanical hyperalgesia in this model for neuropathic pain.
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Randomized Controlled Trial Clinical Trial
Antihyperalgesic effect of the N-methyl-D-aspartate receptor antagonist dextromethorphan in the oral surgery model.
Peripheral neuronal barrage from tissue injury produces central nervous system hyperexcitability through the activation of N-methyl-D-aspartate (NMDA) receptor sites by excitatory amino acids and neuropeptides. This study evaluated if attenuation of NMDA receptor activation with dextromethorphan (DM) suppresses the postoperative development of hyperalgesia. Seventy-five patients undergoing oral surgery in a parallel-group, double-blind study randomly received either a placebo or the maximally tolerated dose of DM administered orally prior to and continuing for 48 hours following surgery. ⋯ Subjects in the DM group also self-administered fewer acetaminophen tablets for unrelieved pain over 24 to 48 hours postoperatively. The results suggest that DM at maximally tolerated doses does not produce an analgesic effect in the immediate postoperative period but reduces pain at 48 hours. This may be related to antagonism of NMDA receptors necessary for the expression of hyperalgesia associated with noxious afferent input postoperatively.
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Reduction of the threshold of cardiovascular and neuronal responses to facial and intracranial stimulation reflects central sensitization and cutaneous allodynia in a rat model of migraine. Current theories propose that migraine pain is caused by chemical activation of meningeal perivascular fibers. We previously found that chemical irritation of the dura causes trigeminovascular fibers innervating the dura and central trigeminal neurons receiving convergent input from the dura and skin to respond to low-intensity mechanical and thermal stimuli that previously induced minimal or no responses. ⋯ The onsets of neuronal responses preceded the onsets of depressor responses by 1.7 s and pressor responses by 4.0 s. The duration of neuronal responses was 15 s, whereas the duration of depressor responses was shorter (5.8 s) and pressor responses longer (22.7 s) than the neuronal responses. We conclude that the facilitated cardiovascular and central trigeminal neuronal responses to innocuous stimulation of the skin indicate that when dural stimulation induces central sensitization, innocuous stimuli are as nociceptive as noxious stimuli had been before dural stimulation and that a similar process might occur during the development of cutaneous allodynia during migraine.