Pain
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Exogenous cannabinoids are effective in attenuating neuropathic pain behaviors induced by peripheral nerve injury, but the mechanisms of their effectiveness remain unclear. Here we examined the expression of spinal cannabinoid-1-receptors (CB1Rs) following chronic constriction sciatic nerve injury (CCI) and its relation to the effects of a CBR agonist (Win 55,212-2) on neuropathic pain in rats. CCI induced a time-dependent upregulation of spinal CB1Rs primarily within the ipsilateral superficial spinal cord dorsal horn as revealed by both Western blot and immunohistochemistry. ⋯ At the intracellular level, the mitogen-activated protein kinase (ERK-MAPK) inhibitor PD98059 (1 microg) prevented, while the protein kinase C inhibitor chelerythrine (10 microg) partially reduced, the CCI-induced CB1R upregulation when each agent was administered intrathecally for postoperative days 1-6. Importantly, the CCI-induced upregulation of spinal CB1Rs enhanced the effects of Win 55,212-2 on both thermal hyperalgesia and mechanical allodynia, since inhibition of the CB1R upregulation by PD98059 resulted in a significant reduction of the effects of Win 55,212-2 in CCI rats. These results indicate that upregulation of spinal CB1Rs following peripheral nerve injury may contribute to the therapeutic effects of exogenous cannabinoids on neuropathic pain.
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Comparative Study
Comparative activity of the anti-convulsants oxcarbazepine, carbamazepine, lamotrigine and gabapentin in a model of neuropathic pain in the rat and guinea-pig.
Anti-epileptic drugs (AEDs) are increasingly used for the treatment of neuropathic pain. Oxcarbazepine is a recently introduced AED that is effective in treating epilepsy and has an improved side-effect profile compared to existing therapies. Here we have examined the effect of oxcarbazepine and other AEDs in a model of neuropathic pain in the rat and guinea-pig. ⋯ Gabapentin was poorly active against mechanical hyperalgesia in both the rat and guinea-pig following a single oral administration (100 mg x kg(-1)), although upon repeated administration it produced up to 70 and 90% reversal in rat and guinea-pig, respectively. Gabapentin did however produce significant dose-related reversal of tactile allodynia in the rat following a single administration. These data show that oxcarbazepine and other AEDs are effective anti-hyperalgesic or anti-allodynic agents in an animal model of neuropathic pain, and provide further support for their use in the treatment of neuropathic pain in the clinic.
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The development of chronic pain after surgery is not rare. Nerve injury from complete or partial nerve section during surgery leads to macrophage recruitment and release of pro-inflammatory cytokines, leading in turn to sensitization. Macrophages also express alpha2-adrenoceptors, and we previously demonstrated a prolonged reduction in hypersensitivity following peri-neural injection of the alpha2-adrenoceptor agonist, clonidine, in rats with chronic nerve injury. ⋯ Clonidine's effects on behavior and TNFalpha content were blocked by BRL44408. We conclude that peri-neural administration of clonidine at the site and time of injury reduces the degree of hypersensitivity in part by altering the balance of pro- and anti-inflammatory cytokines through activation of alpha2A-adrenoceptors. These results support testing of whether clonidine, as an adjuvant in continuous peripheral nerve blocks in settings of known major nerve injury, such as limb amputation, might prevent the development of chronic pain.
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Opioids and cannabinoids produce antinociception through both spinal and supraspinal action. Both opioids and cannabinoids also have important peripheral action. Many previous studies indicate that systemically administered cannabinoids enhance antinociceptive properties of opioids. ⋯ Additionally, spinally administered ineffective doses of WIN 55, 212-2 potentiated the antinociceptive effects of topical morphine. These results demonstrate an antinociceptive interaction between topical opioids with topical, and spinal cannabinoids. These observations are significant in using of topical combination of cannabinoid and morphine in the management of pain.
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Comparative Study
Differential effects of expressive anger regulation on chronic pain intensity in CRPS and non-CRPS limb pain patients.
Research has shown that the anger management styles of both anger-in (suppression of anger) and anger-out (direct verbal or physical expression of anger) may be associated with elevated chronic pain intensity. Only the effects of anger-out appear to be mediated by increased physiological stress responsiveness. Given the catecholamine-sensitive nature of pain mechanisms in complex regional pain syndrome (CRPS), it was hypothesized that anger-out, but not anger-in, would demonstrate a stronger relationship with chronic pain intensity in CRPS patients than in non-CRPS chronic pain patients. ⋯ The AIS main effect on MPQ-A ratings was accounted for entirely by overlap with negative affect. Results are consistent with a greater negative impact of anger-out on chronic pain intensity in conditions reflecting catecholamine-sensitive pain mechanisms, presumably due to the association between anger-out and elevated physiological stress responsiveness. These results further support previous suggestions that anger-in and anger-out may affect pain through different mechanisms.