Articles: neuropathic-pain.
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The aim of this study was to assess the function of the thermo-nociceptive system in 25 patients with long-lasting, medium-to-severe refractory complex regional pain syndrome (CRPS)-1 using behavioral (detection rates and reaction times) and electrophysiological (event-related brain potentials) responses to brief (50 milliseconds) and intense (suprathreshold for Aδ-nociceptors) carbon dioxide laser stimuli delivered to the affected and contralateral limbs, and by comparing these responses to the responses obtained in the left and right limbs of age- and sex-matched healthy controls. Compared with healthy controls and compared with the contralateral limb, the detection rate of pricking pain related to the activation of Aδ-fibers was markedly reduced at the affected limb. Furthermore, reaction times were substantially prolonged (>100 milliseconds in 84% of patients and >300milliseconds in 50% of patients). ⋯ Taken together, our results show that in the majority of patients with chronic CRPS-1, thermo-nociceptive pathways are dysfunctional. A number of pathological mechanisms involving the peripheral nervous system and/or the central nervous system could explain our results. However, the primary or secondary nature of these observed changes remains an open question.
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Peripherally acting opioids are potentially attractive drugs for the clinical management of certain chronic pain states due to the lack of centrally mediated adverse effects. However, it remains unclear whether tolerance develops to peripheral opioid analgesic effects under neuropathic pain conditions. We subjected rats to L5 spinal nerve ligation (SNL) and examined the analgesic effects of repetitive systemic and local administration of loperamide hydrochloride, a peripherally acting opioid agonist. ⋯ However, this drug effect significantly decreased in cells pretreated with loperamide (3 μM, 72 hours). Intriguingly, in loperamide-tolerant cells, the delta-opioid receptor antagonist naltrindole restored loperamide's inhibition of KCl-elicited [Ca(2+)]i increase. Our findings indicate that animals with neuropathic pain may develop acute tolerance to the antiallodynic effects of peripherally acting opioids after repetitive systemic and local drug administration.
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Studies of peripheral nerve inflammation (neuritis) suggest that some symptoms of neuropathic pain can be generated from inflamed but otherwise uninjured axons. We have previously inferred a role for inflammation-induced axonal transport disruption in the underlying mechanisms. In the present study, we have investigated the development of sensory hypersensitivities following vinblastine-induced axonal transport disruption. Similar to neuritis, locally applied .1 mM vinblastine caused the rapid development of mechanical hypersensitivity within the first week postsurgery. The same animals did not develop heat hypersensitivity. Because aberrant firing from primary sensory neurons is considered necessary to drive spinal mechanisms that lead to hypersensitivities, the levels of ongoing activity and axonal mechanical sensitivity were examined. Recordings from A- and C-fiber neurons did not reveal differences in the levels of ongoing activity between vinblastine-treated (<5.8%) and saline-treated control animals (<4.6%). However, 28% of C-fiber axons were mechanically sensitive at the vinblastine treatment site. Using kinesin immunohistochemistry, we confirmed a reduction of anterograde axonal transport in vinblastine-treated and neuritis animals. In summary, this study has revealed an alternative pain model, which may be relevant to conditions that are not accompanied by frank nerve injury. ⋯ In this study, we expand our previous reports and demonstrate that focal reduced axonal transport causes distal mechanical hypersensitivity considered consistent with neuropathic pain but in the absence of nerve injury. These findings may inform pain conditions that have a neural inflammatory component.
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The clinical effects of motor cortex stimulation (MCS) for neuropathic pain (NP) is thought to be mediated primarily by the secretion of endogenous opioids in humans and in animal models. Because opioid receptor density is itself decreased in patients with NP, we investigated whether the magnitude and distribution of the remaining opioid receptors in patients with NP could be biological predictors of the pain-relieving effects of MCS. Using (11)C-diprenorphine positron emission tomography scans, opioid receptor availability was assessed in 15 patients suffering refractory NP, who subsequently received chronically implanted MCS. ⋯ The levels of preoperative opioid-binding in the insula, thalamus, periaqueductal gray, anterior cingulate, and orbitofrontal cortex were significantly and positively correlated with postoperative pain relief at 7mo. Patients with receptor density values below the lower limits in age-matched controls in the thalamus, periaqueductal gray and contralateral insula were the least likely to benefit from MCS. Opioid-receptor availability as shown in preoperative positron emission tomography scans appears to be related to the efficacy of MCS in NP and may help clinicians to select the candidates most likely to benefit from this procedure.
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In the spinal nerve ligation (SNL) model of neuropathic pain, synaptic plasticity shifts the excitation/inhibition balance toward excitation in the spinal dorsal horn. We investigated the deregulation of the synaptogenic neuroligin (NL) molecules, whose NL1 and NL2 isoforms are primarily encountered at excitatory and inhibitory synapses, respectively. In the dorsal horn of SNL rats, NL2 was overexpressed whereas NL1 remained unchanged. ⋯ Expression of the inhibitory scaffolding protein gephyrin remained unchanged, indicating a partial change in NL2 postsynaptic partners in SNL rats. This phenomenon appears to be specific to the NL2(-) isoform. Our data showed unexpected upregulation and pronociceptive effects of the "inhibitory" NL2 in neuropathic pain, suggesting a functional shift of NL2 from inhibition to excitation that changed the synaptic ratio toward higher excitation.