Pain
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This study investigated the effects of pharmacological inhibition of phosphatidylinositol 3-kinase (PI3K)γ in the pruriceptive, inflammatory, and nociceptive responses induced by trypsin in mice. The animals were orally treated with the selective PI3Kγ inhibitor AS605240 (0.3-30 mg/kg) 30 minutes beforehand. In separate groups, AS605240 was given by intrathecal (i.t.) or intracerebroventricular (i.c.v.) routes. ⋯ In contrast, the oral administration of AS605240 did not significantly modify capsaicin-evoked nociception, although this inhibitor was effective when dosed by i.c.v. route. Noteworthy, AS605240 (1mg/kg) was able to prevent c-Fos and phospho-Akt immunopositivity at the spinal cord of trypsin-injected mice, either into the back of the neck or the paws. To conclude, PI3Kγ inhibition might well represent a valuable alternative for treating inflammatory and painful conditions, as well as pruritus.
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The role of muscarinic receptor subtype-1 (M1) in chronic pain is unclear. In an attempt to gain an understanding of its role, we have tested xanomeline, an M1/M4-preferring agonist, together with nonselective (scopolamine and pirenzepine), and selective (MT-7 and MT-3) muscarinic receptor (M1 and M4, respectively) antagonists in a number of inflammatory and neuropathic pain models. Xanomeline potently and effectively reversed tactile allodynia and heat hyperalgesia associated with established neuropathic and inflammatory pain in both rat and mouse models. ⋯ The highly selective M1 receptor toxin, MT-7, almost completely abolished the analgesic response to xanomeline when administered supraspinally. However, the highly selective M4 receptor toxin, MT-3, only marginally reversed the analgesia when given supraspinally, and had no effect when given spinally. In conclusion, the data presented show that the nonselective muscarinic agonist xanomeline is analgesic in models of persistent pain and suggest that the activation of supraspinal M1 receptors, and to a lesser extent supraspinal M4 receptors, contributes to that analgesia.
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Comparative Study
Engagement of descending inhibition from the rostral ventromedial medulla protects against chronic neuropathic pain.
A puzzling observation is why peripheral nerve injury results in chronic pain in some, but not all, patients. We explored potential mechanisms that may prevent the expression of chronic pain. Sprague Dawley (SD) or Holtzman (HZ) rats showed no differences in baseline sensory thresholds or responses to inflammatory stimuli. ⋯ Thus, expression of nerve injury-induced pain may ultimately depend on descending modulation. Engagement of descending inhibition protects in the transition from acute to chronic pain. These unexpected findings might provide a mechanistic explanation for medications that engage descending inhibition or mimic its consequences.
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Multicenter Study
The mediating role of pain in substance use and depressive symptoms among Multicenter AIDS Cohort Study (MACS) participants.
Pain in human immunodeficiency virus (HIV) frequently co-occurs with substance use and depression. The complex associations among patient characteristics, pain, depression, and drug use in HIV suggests a role for testing models that can account for relationships simultaneously, control for HIV status, and also test for mediation. Using structural equation modeling, the current study examined associations among pain, sociodemographics, illicit drug use, and depressive symptoms in 921 HIV-seropositive and 1019 HIV-seronegative men from the Multicenter AIDS Cohort Study, an ongoing prospective study of the natural history of HIV infection among gay/bisexual men. ⋯ HIV-seropositive status predicted more use of inhaled nitrites. In this cohort, having lower CD4+ cell counts (predicted by HIV status), being African American, less educated, and older were all associated with more pain, which, in turn, was associated with more illicit drug use and more depressive symptoms. The results underscore the need for adequate pain management, particularly among vulnerable subgroups of HIV-seropositive and HIV-seronegative men to reduce the risk of drug use and depression.