Pain
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Pharmacological blockade of N-methyl-D-aspartate (NMDA) receptors can modulate morphine analgesia in experimental animals and humans. However, this literature is highly inconsistent, with NMDA receptor antagonists variously shown to potentiate, attenuate or produce no effect on morphine analgesic magnitude. A number of factors influencing this modulation have been proposed, but no one has examined such factors simultaneously, and all existing studies in mice were conducted exclusively in male subjects. ⋯ Strikingly, the non-competitive antagonists produced no modulation of morphine analgesia whatsoever in female mice, whereas no sex differences were observed using competitive or NR2B antagonists. These findings indicate that NMDA modulation of morphine analgesia is critically influenced by sex, site of antagonism, morphine dose and time after injection. Our data suggest that NMDA antagonism via competitive or glycine site antagonism might result in more reliable clinical effects on morphine analgesia in both sexes.
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It is generally believed that nerve injury results in neuronal hyperexcitability that reflects in part a change in Na+ currents. However, there are conflicting data on the nature of Na+ current changes and the association between alterations in Na+ currents and increases in excitability. One potential source of conflicting data is that injured and spared neurons may respond differently to nerve injury; these subpopulations of neurons have not been distinguished in previous studies with the axotomy model of nerve injury (complete transection of the sciatic nerve). ⋯ Thus, axotomy-induced changes in Na+ currents were not correlated with an axotomy-induced change in excitability. Additional analysis of axotomized neurons suggested that concomitant changes in other ionic currents occurred. These results suggest that neuronal excitability following axotomy is dependent on the sum of changes in ionic currents, and the overall effect on excitability may not always correspond to that predicted by a change in a single class of voltage-gated ion channel.
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Previous studies from our laboratory have demonstrated that both chronic inflammatory pain, induced by intraplantar injection of complete Freund's adjuvant (CFA), and prolonged (48 h) stimulation of mu-opioid receptors (muOR) by systemic administration of a variety of selective agonists, resulted in enhanced plasma membrane targeting of delta-opioid receptors (deltaOR) in neurons of the dorsal spinal cord. To determine whether deltaOR trafficking induced by chronic inflammation was dependent on the activation of muOR, we investigated by immunogold cytochemistry the effects of intraplantar CFA injection on the plasma membrane density of deltaOR in muOR knockout (KO) mice. In untreated wild-type (WT) mice, only a small proportion of deltaOR was associated with neuronal plasma membranes in the dorsal horn of the spinal cord. ⋯ This increase in the membrane density of deltaOR was likely due to a recruitment of receptors from intracellular stores since no difference in the overall deltaOR immunolabeling density was evident between CFA-treated and untreated mice. Most importantly, the CFA-induced changes in deltaOR plasma membrane insertion seen in WT animals were not present in the spinal cord of muOR KO mice. These results demonstrate that the integrity of muOR is necessary for CFA-induced changes in deltaOR trafficking to occur and suggest that these changes could be elicited by stimulation of muOR by endogenous opioids released in response to chronic inflammatory pain.
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Melatonin, its agonists/antagonists were administered intrathecally (i.t.) before/after intradermal injection of capsaicin. Capsaicin produced an increase in the paw withdrawal frequency (PWF) in the presumed area of secondary mechanical allodynia and hyperalgesia. Melatonin agonists in the absence of a capsaicin injection decreased the PWF significantly, whereas melatonin antagonists given intrathecally alone were ineffective in the absence of a capsaicin injection. ⋯ In spinal rats, the data showed comparable effects of melatonin analogs on capsaicin-induced secondary mechanical hyperalgesia. Animal motor function tested by 'activity box' showed that motion activity was not affected by i.t. melatonin or its antagonist. These results suggest that activation of the endogenous melatonin system in the spinal cord can reduce the generation, development and maintenance of central sensitization, with a resultant inhibition of capsaicin-induced secondary mechanical allodynia and hyperalgesia.
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Capsaicin antagonists including ruthenium red, capsazepine and iodo-resiniferatoxin (I-RTX) have recently been shown to inhibit the activation by noxious heat of the capsaicin receptor (TRPV1) expressed in non-neuronal host cells, and natively, in cultured dorsal root ganglion cells. Noxious heat has been shown to release immunoreactive calcitonin gene-related peptide (iCGRP) from the isolated rat skin. In this model, ruthenium red, I-RTX as well as capsazepine 10 microM caused no alteration in iCGRP release at 32 degrees C by themselves whereas capsazepine 100 microM doubled it reversibly. ⋯ Ruthenium red and capsazepine (10/100 microM) caused no significant alteration of iCGRP release induced by heat stimulation at 47 degrees C. Employing 45 degrees C stimulation intensity, capsazepine and I-RTX (in the higher concentrations) showed a significant facilitatory effect on the heat response suggesting a partial agonistic action of the compounds. It is concluded that noxious heat-induced iCGRP release in the isolated rat skin occurs through a mechanism that is not inhibited by TRPV1 antagonism reflecting a different pharmacological profile of noxious heat transduction in terminals of sensory neurons compared to that in cultured cell bodies and TRPV1-transfected host cells.