Pain
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This study investigated the role of TRPA1 in the development and maintenance of mechanical and cold hyperalgesia in persistent inflammation induced by Complete Freund's Adjuvant (CFA) in mice. The intraplantar (i.pl.) injection of CFA induced a long lasting (28 days) hyperalgesia for both mechanical and thermal (cold) stimuli. The intraperitoneal (i.p., 30-300 mg/kg), intraplantar (i.pl., 100 microg/site) or intrathecal (i.t., 10 microg/site) injection of the TRPA1 selective antagonist HC-030031 significantly reduced the mechanical hyperalgesia evaluated by the von Frey hair test. ⋯ Interestingly, both TRPA1 protein expression and mRNA were over-expressed in spinal cord and dorsal root ganglia (DRG) of mice treated with CFA, an effect that was fully prevented by the pre-treatment with the TRPA1 antagonist HC-030031. Collectively, the present results showed that TRPA1 present at either peripheral or spinal sites play a relevant role in the development and maintenance of both mechanical and cold hyperalgesia during CFA-induced inflammation. Thus, TRPA1 selective antagonists represent promising candidates to treat hyperalgesia in persistent inflammatory states.
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Previous investigations of somatic hypersensitivity in IBS patients have typically involved only a single stimulus modality, and little information exists regarding whether patterns of somatic pain perception vary across stimulus modalities within a group of patients with IBS. Therefore, the current study was designed to characterize differences in perceptual responses to a battery of noxious somatic stimuli in IBS patients compared to controls. A total of 78 diarrhea-predominant and 57 controls participated in the study. ⋯ The somatic hypersensitivity in IBS patients was somatotopically organized in that the lower extremities that share viscerosomatic convergence with the colon demonstrate the greatest hypersensitivity. There were also changes in ACTH, cortisol, and systolic blood pressure in response to the ischemic pain testing in IBS patients when compared to controls. The results of this study suggest that a more widespread alteration in central pain processing in a subset of IBS patients may be present as they display hypersensitivity to heat, ischemic, and cold pressor stimuli.
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Pain following injury to the nervous system is characterized by changes in sensory processing including pain. Although there are many studies describing pain evoked by peripheral stimulation, we have recently reported that pain can be evoked in subjects with complete spinal cord injury (SCI) during a motor imagery task. In this study, we have used functional magnetic resonance imaging to explore brain sites underlying the expression of this phenomenon. ⋯ In addition, in the SCI subjects, the magnitude of activation in the perigenual anterior cingulate cortex and right dorsolateral prefrontal cortex was significantly correlated with absolute increases in pain intensity. These regions expanded to include right and left anterior insula, supplementary motor area and right premotor cortex when percentage change in pain intensity was examined. This study demonstrates that in SCI subjects with neuropathic pain, a cognitive task is able to activate brain circuits involved in pain processing independently of peripheral inputs.
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Injection of nerve growth factor (NGF) into the masseter muscle is not painful but does induce a localized, quick onset ( approximately 1h) and long-lasting mechanical sensitization in healthy human subjects. We tested the hypothesis that human NGF mechanically sensitizes masseter muscle nociceptors by increasing the sensitivity of peripheral N-methyl-d-aspartate (NMDA) receptors. Co-expression of the NR2B subunit of the NMDA receptor with P75 and TrkA NGF receptors by trigeminal ganglion neurons that innervate the masseter muscle was investigated immunohistochemically. ⋯ There was no effect of NGF on glutamate-evoked nociceptor discharge or glutamate-induced mechanical sensitization. Additional experiments indicated that NGF-induced mechanical sensitization could be partially attenuated with TrkA receptor antibodies, but not P75 receptor antibodies. These findings indicate that human NGF-induced sensitization of masseter nociceptors results, in part, from the activation of TrkA receptors, but does not appear to be mediated through enhanced peripheral NMDA receptor activity.
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Current clinical treatments for neuropathic pain include amitriptyline, a tricyclic antidepressant with mixed pharmacology that is also clinically reported to impair cognitive performance; and gabapentin, a compound that selectively interacts with alpha2delta-1 calcium channel subunits. Since few assessments of cognitive performance have been made in non-human primates with these marketed treatments, the purpose of this study was to determine their relative abilities to alter working memory as measured in mature macaques in their performance of a delayed matching-to-sample task. Four delay intervals of increasing duration provided increasing impairment in task accuracies during vehicle sessions. ⋯ In a series that used a task-relevant distractor to determine gabapentin's effect on attention, drug treatment reversed distractor-impaired accuracy during long delay trials (25.4% above vehicle). The selective improvement in long delay accuracy in both paradigms suggests improvement in encoding or retention components of working memory. It is currently unclear whether the ability of acute administration of gabapentin to modestly improve working memory occurs by a mechanism that could be related to its anti-allodynic mechanism of action.