Pain
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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.
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Clinical Trial
The evaluation of acute pain in individuals with cognitive impairment: a differential effect of the level of impairment.
The present study investigated whether the level of cognitive impairment (CI) affects acute pain behavior and how it is manifested. Participants were 159 individuals (mean age 42+/-12), 121 with CI (divided into four groups according to the level of CI: mild, moderate, severe, profound) and 38 with normal cognition (controls). The behavior of the participants before and during acute pain (influenza vaccination) was coded by two raters with the Facial Action Coding System (FACS - scores facial reactions to pain) and the Non-Communicating Children's Pain Checklist (NCCPC-R - scores both facial and general body reactions). ⋯ In contrast, individuals with severe-profound CI exhibited high rates of "freezing reaction" (stillness) during vaccination, manifested mainly in the face and therefore resulting in elevation of only NCCPC-R scores but not of FACS's. The results suggest that the level of CI affects baseline as well as pain behavior and it is therefore necessary to choose an appropriate behavioral tool to measure pain in these individuals accordingly. For example, tools based on facial reactions alone might provide the false impression that individuals with severe-profound CI are insensitive to pain (due to freezing).
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Suggestion for hypnotic analgesia aimed at a specific body area is termed "focused hypnotic analgesia". It is not clear, however, whether this analgesia is limited to a specific body location or spread all over the body. Focused hypnotic analgesia was studied, in response to ascending electrical stimuli, when analgesia and stimulation were applied to the same area (local), and when analgesia was applied to one location and stimulation was delivered to a different area (remote). ⋯ We conclude that in HH subjects focused hypnotic analgesia is mostly confined to the area aimed at, but some spread of analgesia to remote areas cannot be dismissed all together. Alternatively, this "spread" of analgesia could be due to a placebo effect in the remote area. Focused hypnotic analgesia requires increased attention to the body area aimed at, unlike analgesia achieved by distraction of attention.