Pain
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Glycine inhibitory dysfunction provides a useful experimental model for studying the mechanism of dynamic mechanical allodynia, a widespread and intractable symptom of neuropathic pain. In this model, allodynia expression relies on N-methyl-d-aspartate receptors (NMDARs), and it has been shown that astrocytes can regulate their activation through the release of the NMDAR coagonist d-serine. Recent studies also suggest that astrocytes potentially contribute to neuropathic pain. ⋯ These results suggest the following scenario: removal of glycine inhibition makes tactile stimuli able to activate astrocytes; activated astrocytes may provide d-serine to enable NMDAR activation and thus allodynia. Such a contribution of astrocytes to pathological pain fuels the emerging concept that astrocytes are critical players in pain signaling. Glycine disinhibition makes tactile stimuli able to activate astrocytes, which may provide d-serine to enable NMDA receptor activation and thus allodynia.
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It has been proposed that goal pursuit plays a role in the development of chronic pain disorders. On the basis of (affective) motivational theories, it was hypothesized that both long-term achievement goals and short-term hedonic goals would be related to increased levels of pain and disability, particularly in patients with high negative affect. Participants with musculoskeletal pain complaints (N=299) completed a battery of questionnaires including a novel goal pursuit questionnaire (GPQ) measuring the extent to which participants preferred hedonic goals (mood-management or pain-avoidance goals) over achievement goals in various situations. ⋯ These findings provide support for the validity of an affective-motivational approach to chronic pain, suggesting that the experience of pain and the interference of pain on daily life activities depends on goal pursuit and negative affect. Interventions aimed at improving disability in chronic pain should address both patient's goal pursuit and negative affect. An affective-motivational approach to chronic pain indicates that achievement and pain-avoidance goals are associated with pain severity and disability, particularly in patients with high negative affect.
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The development of new strategies for the treatment of acute pain requires the identification of novel nonopioid receptor targets. This study explored whether δ-subunit-containing GABA(A)Rs (δGABA(A)Rs) in neurons of the spinal cord dorsal horn generate a tonic inhibitory conductance in vitro and whether δGABA(A)R activity regulates acute nociception. Whole-cell recordings revealed that δGABA(A)Rs generate a tonic inhibitory conductance in cultured spinal neurons and lamina II neurons in spinal cord slices. ⋯ Surprisingly, THIP reduced the enhanced phase 2 response in Gabrd(-/-) mice. Together, these results suggest that δGABA(A)Rs in spinal neurons play a major physiological and pharmacological role in the regulation of acute nociception and central sensitization. Spinal δ-subunit-containing GABA(A) receptors were identified with electrophysiological methods and behavioral models as novel targets for the treatment of acute pain.