Pain
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Chronic neuropathic pain may be caused, in part, by loss of inhibition in spinal pain processing pathways due to attenuation of local GABAergic tone. Nociception and nocifensive behaviors are reduced after enhancement of tonically activated extrasynaptic GABAAR-mediated currents by agonist ligands for δ subunit-containing GABAARs. However, typical ligands that target δ subunit-containing GABAARs are limited due to sedative effects at higher doses. ⋯ Moreover, 2-261 reversed thermal hyperalgesia and partially reversed tactile allodynia in the gp120 model of HIV-related neuropathic pain. The effects of 2-261 likely required interaction with the α4β3δ GABAAR because 2-301, a close structural analog of 2-261 with limited extrasynaptic receptor efficacy, was not active. Thus, 2-261 may produce pain relief with diminished side effects through selective modulation of β2/3-subunit-containing extrasynaptic GABAARs.
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Cancer-induced bone pain is abundant among advanced-stage cancer patients and arises from a primary tumor in the bone or skeletal metastasis of common cancer types such as breast, lung, or prostate cancer. Recently, antibodies targeting nerve growth factor (NGF) have been shown to effectively relieve neuropathic and inflammatory pain states in mice and in humans. Although efficacy has been shown in mice on a behavioral level, effectiveness in preventing pain-induced functional rearrangements in the central nervous system has not been shown. ⋯ These changes could be successfully prevented through prospective administration of a monoclonal anti-NGF antibody (mAb911). This indicates efficacy of anti-NGF treatment to prevent pain-induced adaptations in brain functional networks after persistent nociceptive input from cancer-induced bone pain. In addition, it highlights the suitability of resting-state functional magnetic resonance imaging readouts as an indicator of treatment response on the basis of longitudinal functional network changes.
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Recent studies have suggested a sexually dimorphic role of spinal glial cells in the maintenance of mechanical hypersensitivity in rodent models of chronic pain. We have used the collagen antibody-induced arthritis (CAIA) mouse model to examine differences between males and females in the context of spinal regulation of arthritis-induced pain. We have focused on the late phase of this model when joint inflammation has resolved, but mechanical hypersensitivity persists. ⋯ Taken together, these findings suggest that there are subtle sex differences in microglial expression profiles independent of arthritis. Our experiments failed to identify the underlying mRNA correlates of microglial actions in the late phase of the CAIA model. It is likely that transcriptional changes are either subtle and highly localised and therefore difficult to identify with bulk isolation techniques or that other factors, such as changes in protein expression or epigenetic modifications, are at play.
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Clinical studies indicate that cannabidiol (CBD), the primary nonaddictive component of cannabis that interacts with the serotonin (5-HT)1A receptor, may possess analgesic and anxiolytic effects. However, its effects on 5-HT neuronal activity, as well as its impact on models of neuropathic pain are unknown. First, using in vivo single-unit extracellular recordings in rats, we demonstrated that acute intravenous (i.v.) increasing doses of CBD (0.1-1.0 mg/kg) decreased the firing rate of 5-HT neurons in the dorsal raphe nucleus, which was prevented by administration of the 5-HT1A antagonist WAY 100635 (0.3 mg/kg, i.v.) and the TRPV1 antagonist capsazepine (1 mg/kg, i.v.) but not by the CB1 receptor antagonist AM 251 (1 mg/kg, i.v.). ⋯ Seven days of treatment with CBD reduced mechanical allodynia, decreased anxiety-like behavior, and normalized 5-HT activity. Antiallodynic effects of CBD were fully prevented by capsazepine (10 mg/kg/day, s.c., for 7 days) and partially prevented by WAY 100635 (2 mg/kg/day, s.c., for 7 days), whereas the anxiolytic effect was blocked only by WAY. Overall, repeated treatment with low-dose CBD induces analgesia predominantly through TRPV1 activation, reduces anxiety through 5-HT1A receptor activation, and rescues impaired 5-HT neurotransmission under neuropathic pain conditions.
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The International Classification of Diseases, 11th Revision (ICD-11), proposes, for the first time, a coding system for chronic pain. This system contains 1 code for "chronic primary pain," where chronic pain is the disease, and 6 codes for chronic secondary pain syndromes, where pain developed in the context of another disease. This provides the opportunity for routine, standardised coding of chronic pain throughout all health care systems. ⋯ Chronic pain will be recognized as a centrally important condition in primary care. The capacity to measure incidence, prevalence, and impact will help in identification of human, financial, and educational needs required to address chronic pain in primary care. Finally, opportunities to match evidence-based treatment pathways to distinct chronic pain subtypes will be enhanced.