The journal of pain : official journal of the American Pain Society
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Randomized Controlled Trial
Pharmacological modulation of the mitochondrial electron transport chain in paclitaxel-induced painful peripheral neuropathy.
Paclitaxel is an effective first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Mitochondrial dysfunction and oxidative stress have been implicated in paclitaxel-induced painful neuropathy. Here we show the effects of pharmacological modulation of mitochondrial sites that produce reactive oxygen species using systemic rotenone (complex I inhibitor) or antimycin A (complex III inhibitor) on the maintenance and development of paclitaxel-induced mechanical hypersensitivity in adult male Sprague Dawley rats. The maximally tolerated dose (5 mg/kg) of rotenone inhibited established paclitaxel-induced mechanical hypersensitivity. However, some of these inhibitory effects coincided with decreased motor coordination; 3 mg/kg rotenone also significantly attenuated established paclitaxel-induced mechanical hypersensitivity without any motor impairment. The maximally tolerated dose (.6 mg/kg) of antimycin A reversed established paclitaxel-induced mechanical hypersensitivity without any motor impairment. Seven daily doses of systemic rotenone or antimycin A were given either after paclitaxel administration or before and during paclitaxel administration. Rotenone had no significant effect on the development of paclitaxel-induced mechanical hypersensitivity. However, antimycin A significantly inhibited the development of paclitaxel-induced mechanical hypersensitivity when given before and during paclitaxel administration but had no effect when given after paclitaxel administration. These studies provide further evidence of paclitaxel-evoked mitochondrial dysfunction in vivo, suggesting that complex III activity is instrumental in paclitaxel-induced pain. ⋯ This study provides further in vivo evidence that mitochondrial dysfunction is a key contributor to the development and maintenance of chemotherapy-induced painful neuropathy. This work also indicates that selective modulation of the electron transport chain can induce antinociceptive effects in a preclinical model of paclitaxel-induced pain.
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SCN9A is a key player in various rare monogenic pain disorders, including absence of pain or extreme pain, indicating that SCN9A is critical in human pain perception. This study aimed to investigate the association between the single-nucleotide polymorphisms (SNPs) in SCN9A and basal pain sensitivity variability in the general population. We used a combined tag and candidate SNP approach to explore possible associations between SCN9A SNPs and basal pain sensitivity in 309 healthy female Chinese undergraduates. Mechanical and heat pain sensitivity were measured, and a total of 28 SNPs were included in the final correlation analysis. Four candidate SNPs (rs6746030, rs7595255, rs12622743, and rs11898284) and 10 tag SNPs were associated (P < .05) with different pain perception phenotypes and exhibited opposite effects, resulting in either hypersensitivity or hyposensitivity. Furthermore, of all these SNPs, rs16851778 showed the strongest significant (P = .003) association with lower mechanical pain sensitivity, which was strengthened in a subsequent replication sample with 260 young patients scheduled for elective gynecological surgery. These findings provided evidence that the variability of basal pain sensitivity was associated with SCN9A polymorphisms in the general population. ⋯ This study demonstrated that several candidate and tag SCN9A SNPs were associated with hypersensitivity or hyposensitivity to basal experimental pain stimulation. Moreover, we identified a novel SNP, i,e,, rs16851778, that was associated with lower mechanical pain sensitivity and that was strengthened in a subsequent replication sample.
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Many studies have found evidence of conditioning-induced nocebo hyperalgesia. However, these studies have exclusively involved continuous reinforcement (CRF) schedules. Thus, it is currently unknown whether nocebo hyperalgesia can result after partial reinforcement (PRF). We tested this using electrodermal pain stimulation in healthy volunteers. Undergraduates (N = 135) received nocebo treatment under the guise of a hyperalgesic. Participants were randomly allocated to CRF, PRF, or control (no conditioning). Conditioning involved surreptitiously increasing pain stimulation on nocebo trials relative to control trials. During training, the CRF group always had the nocebo paired with the surreptitious pain increase, whereas the PRF group experienced the increase on only 62.5% of nocebo trials. In the test phase, pain stimulation was equivalent across nocebo and control trials. PRF was sufficient to induce nocebo hyperalgesia; however, this was weaker than CRF. Nocebo hyperalgesia failed to extinguish irrespective of the training schedule. Additional assessment of expectancies indicated strong concordance between expectancy and nocebo hyperalgesia. Overall, these findings suggest that once established, nocebo hyperalgesia may be difficult to disrupt. PRF may be a novel method of reducing the intensity of nocebo hyperalgesia in the clinic, which may be particularly important given its persistence. ⋯ This study provides novel evidence that partial reinforcement results in weaker nocebo hyperalgesia than continuous reinforcement and that nocebo hyperalgesia fails to extinguish, irrespective of the training schedule. As a result, partial reinforcement may serve as a method for reducing the intensity of nocebo hyperalgesia in the clinic.
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This study sought to estimate (1) the prevalence of the co-occurrence of, (2) the association between, and (3) the sequence of onset of chronic pain and mental disorders in adolescents. We used weighted data (N = 6,483) from the National Comorbidity Survey Replication Adolescent Supplement (participants' age, 13-18 years). Lifetime chronic pain was assessed by adolescent self-report; lifetime DSM-IV mental disorders were assessed by the WHO Composite International Diagnostic Interview, complemented by parent report. Among the participants in the study, 1,600 of 6,476 (25.93%) had experienced any type of chronic pain and any mental disorder in their lifetime. All types of pain were related to mental disorders. The most substantial temporal associations were those with onset of mental disorders preceding onset of chronic pain, including those between affective disorders and headaches and any chronic pain; between anxiety disorders and chronic back/neck pain, headaches, and any chronic pain; between behavior disorders and headaches and any chronic pain; and between any mental disorder and chronic back/neck pain, headaches, and any chronic pain. ⋯ Findings indicate that affective, anxiety, and behavior disorders are early risk factors of chronic pain, thereby highlighting the relevance of child mental disorders for pain medicine. To improve prevention and interventions for chronic pain, integrative care should be considered.
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Posttraumatic stress disorder (PTSD) and chronic pain often co-occur and exacerbate each other. Elucidating the mechanism of this co-occurrence therefore has clinical importance. Previously, patients with PTSD with chronic pain were found to demonstrate a unique paradoxical pain profile: hyperresponsiveness together with hyposensitivity to pain. Our aim was to examine whether 2 seemingly paradoxical facets of PTSD (anxiety and dissociation) underlie this paradoxical profile. Patients with PTSD (n = 32) and healthy control individuals (n = 43) underwent psychophysical testing and completed questionnaires. Patients with PTSD had higher pain thresholds and higher pain ratings to suprathreshold stimuli than control individuals. Pain thresholds were positively associated with dissociation levels and negatively associated with anxiety sensitivity levels. Experimental pain ratings were positively associated with anxiety sensitivity and negatively related to dissociation levels. Chronic pain intensity was associated with anxiety, anxiety sensitivity, and pain catastrophizing. It appears that reduced conscious attention toward incoming stimuli, resulting from dissociation, causes delayed response in pain threshold measurement, whereas biases toward threatening stimuli and decreased inhibition, possibly caused by increased anxiety, are responsible for the intensification of experimental and chronic pain. The paradoxical facets of PTSD and their particular influences over pain perception seem to reinforce the coexistence of PTSD and chronic pain, and should be considered when treating traumatized individuals. ⋯ This article provides new information regarding the underlying mechanism of the coexistence of PTSD and chronic pain. This knowledge could help to provide better management of PTSD and chronic pain among individuals in the aftermath of trauma.