Pain
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Randomized Controlled Trial Clinical Trial
Opposite effects of opioid blockade on the blood pressure-pain relationship in depressed and non-depressed participants.
The effect of the opioid antagonist naltrexone on the relationship between blood pressure and pain was examined in 24 participants with major depressive disorder and 31 non-depressed controls, before and after 25 min of stressful mental arithmetic. Pain was induced by immersing the non-dominant foot in 2 degrees C ice-water for as long as possible or until 4 min had elapsed (the cold pressor test). Blood pressure was measured before each cold pressor test, and at 2-min intervals during mental arithmetic. ⋯ However, naltrexone unmasked an association between blood pressure and pain--those with highest blood pressure reported least cold-induced pain. Thus, endogenous opioids apparently masked an analgesic mechanism linking elevated blood pressure with reduced sensitivity to pain in participants with major depressive disorder. Noradrenergic mechanisms involved in active coping, stress-induced analgesia and baroreflexes might account for these findings.
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We have developed a model in which inflammation contiguous to and within a dorsal root ganglion (DRG) was generated by local application of complete Freund's adjuvant (CFA) to the L4 lumbar spinal nerve as it exits from the intervertebral foramen. The periganglionic inflammation (PGI) elicited a marked reduction in withdrawal threshold to mechanical stimuli and an increase in heat pain sensitivity in the ipsilateral hindpaw in the absence of any hindpaw inflammation. The pain sensitivity appeared within hours and lasted for a week. ⋯ We also show that IL-1beta induces COX-2 expression and prostaglandin release in DRG neurons in vitro in a MAP kinase-dependent fashion. The COX-2 induction was prevented by ERK and p38 inhibitors. We conclude that periganglionic inflammation increases cytokine levels, including IL-1beta, leading to the transcription of COX-2 and prostaglandin production in the affected DRG, and thereby to the development of a dermatomally distributed pain hypersensitivity.
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We investigated the participation of cyclin-dependent kinase-5 (Cdk5)-mediated N-methyl-D-aspartate receptor (NMDAR) NR2B subunit phosphorylation in cross-organ reflex sensitization caused by colon irritation. The external urethral sphincter electromyogram (EUSE) reflex activity evoked by the pelvic afferent nerve test stimulation (TS, 1 stimulation/30s) and protein expression in the spinal cord and dorsal root ganglion tissue (T13-L2 and L6-S2 ipsilateral to the stimulation) in response to colon mustard oil (MO) instillation were tested in anesthetized rats. ⋯ Moreover, compared with the control group, both the increase in pNR2B and the cross-organ reflex sensitization were attenuated in the si-RNA of NR2B rats. All these results suggested that Cdk-dependent NMDAR NR2B subunit phosphorylation mediates the development of cross-organ pelvic-urethra reflex sensitization caused by acute colon irritation which could possibly underlie the high concurrence of pelvic pain syndrome with irritable bowel syndrome.
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Hydrogen sulfide (H2S), a gasotransmitter, facilitates membrane currents through T-type Ca2+ channels, and intraplantar (i.pl.) administration of NaHS, a donor of H2S, causes prompt hyperalgesia in rats. In this context, we asked whether intrathecal (i.t.) administration of NaHS could mimic the hyperalgesic effect of i.pl. NaHS in rats, and then examined if Cav3.2 isoform of T-type Ca2+ channels contributed to the pro-nociceptive effects of i.t. and i.pl. ⋯ Repeated i.t. administration of antisense oligodeoxynucleotides (ODNs) targeting rat Cav3.2, but not mismatch ODNs, caused silencing of Cav3.2 protein in the dorsal root ganglia and spinal cord, and then attenuated the hyperalgesia induced by either i.t. or i.pl. NaHS. Our findings thus establish that spinal and peripheral NaHS/H2S activates or sensitizes Cav3.2 T-type Ca2+ channels expressed in the primary afferents and/or spinal nociceptive neurons, leading to sensitization of nociceptive processing and hyperalgesia.