Pain
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We conducted a retrospective analysis of long-term results of deep brain stimulation (DBS) for the treatment of neuropathic pain. Twenty-one patients had electrodes implanted in the ventrocaudalis thalamic nucleus (Vc) (n=13) or in both Vc and periaqueductal/periventricular gray matter (PAG/PVG) (n=8). After insertion of the electrodes, 9 patients (43%) had a substantial reduction in pain scores in the absence of stimulation (insertional effect). ⋯ Of the 13 patients that received an IPG, 8 discontinued stimulation during the first year of treatment. Only 5 patients maintained long-term benefit (4 with stimulation in Vc and one in both Vc and PAG/PVG). The relatively low efficacy of DBS for the treatment of neuropathic pain stresses the need for further investigation and the exploration of new surgical targets.
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Spinally released dynorphin contributes to hypersensitivity from nerve injury, inflammation, and sustained morphine treatment, but its role in post-operative pain has not been tested. Intrathecal injection of dynorphin activates cyclooxygenase (COX)-1 and -2 to induce hypersensitivity. Spinal COX-1 expression and activity increase following incisional paw surgery in rats, although the stimulus for this increase is not known. ⋯ Spinal cord microglia in culture expressed COX-1 immunoreactivity and released PGE2, but dynorphin A failed to increase release of PGE2 in these cultures. These results suggest that increased COX-1 expression occurs in spinal cord microglia following incisional surgery. Although prodynorphin immunoreactivity also increases, it likely does not drive COX-1 expression or mechanical hypersensitivity in this setting.
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Mechanisms of chronic pain, including neuropathic pain, are poorly understood. Upregulation of voltage-gated calcium channel (VGCC) alpha2delta1 subunit (Ca(v)alpha2delta1) in sensory neurons and dorsal spinal cord by peripheral nerve injury has been suggested to contribute to neuropathic pain. To investigate the mechanisms without the influence of other injury factors, we have created transgenic mice that constitutively overexpress Ca(v)alpha2delta1 in neuronal tissues. ⋯ In addition, gabapentin blocked VGCC currents concentration-dependently in transgenic, but not wild-type, sensory neurons. Thus, elevated neuronal Ca(v)alpha2delta1 contributes to specific pain states through a mechanism mediated at least partially by enhanced VGCC activity in sensory neurons and hyperexcitability in dorsal horn neurons in response to peripheral stimulation. Modulation of enhanced VGCC activity by gabapentin may underlie at least partially its antihyperalgesic actions.
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Gabapentin and pregabalin have been demonstrated, both in animal pain models and clinically, to be effective analgesics particularly for the treatment of neuropathic pain. The precise mechanism of action for these two drugs is unknown, but they are generally believed to function via initially binding to the alpha2delta subunit of voltage-gated Ca2+ channels. In this study, we used a pharmacological approach to test the hypothesis whether high affinity interactions with the alpha2delta subunit alone could lead to attenuation of neuropathic pain in rats. ⋯ In contrast, two ligands with comparable or superior alpha2delta binding affinities, m-chlorophenylglycine (Ki = 54 nM) and ABHCA (150 nM), exhibited no anti-allodynic effects at doses of 30-300 micromol/kg (p.o.), although these compounds achieved substantial brain levels. The data demonstrate that, at least in the rat spinal nerve ligation model of neuropathic pain, (L)-phenylglycine has an anti-allodynic effect, but two equally potent alpha2delta subunit ligands do not. These results suggest that additional mechanisms, besides alpha2delta interactions, may contribute to the effects of compounds like gabapentin, pregabalin and (L)-phenylglycine in neuropathic pain.