The journal of pain : official journal of the American Pain Society
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Peripheral nerve injury generally results in spinal neuronal and glial plastic changes associated with chronic behavioral hypersensitivity. Spinal mitogen-activated protein kinases (MAPKs), eg, p38 or extracellular signal-regulated kinases (ERKs), are instrumental in the development of chronic allodynia in rodents, and new p38 inhibitors have shown potential in acute and neuropathic pain patients. We have previously shown that the cannabinoid type 2 receptor agonist JWH015 inhibits ERK activity by inducing MAPK phosphatase (MKP)-1 and MKP-3 (the major regulators of MAPKs) in vitro in microglial cells. Therefore, we decided to investigate the role of these phosphatases in the mechanisms of action of JWH015 in vivo using the rat L5 nerve transection model of neuropathic pain. We observed that peripheral nerve injury reduced spinal MKP-1/3 expression and activity and that intrathecal JWH015 reduced established L5 nerve injury-induced allodynia, enhanced spinal MKP-1/3 expression and activity, and reduced the phosphorylated form of p38 and ERK-1/2. Triptolide, a pharmacological blocker of MKP-1 and MKP-3 expression, inhibited JWH015's effects, suggesting that JWH015 exerts its antinociceptive effects by modulating MKP-1 and MKP-3. JWH015-induced antinociception and MKP-1 and MKP-3 expression were inhibited by the cannabinoid type 2 receptor antagonist AM630. Our data suggest that MKP-1 and MKP-3 are potential targets for novel analgesic drugs. ⋯ MAPKs are pivotal in the development of chronic allodynia in rodent models of neuropathic pain. A cannabinoid type 2 receptor agonist, JWH015, reduced neuropathic allodynia in rats by reducing MAPK phosphorylation and inducing spinal MAPK phosphatases 1 and 3, the major regulators of MAPKs.
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The cold pressor task (CPT) is an ethical experimental pain task widely used by pediatric pain researchers to examine a variety of important theoretical and clinical questions. The purpose of this systematic review was to describe contemporary use of the CPT in pediatric pain research to identify possible methodological and procedural inconsistencies and inform future research. All papers using the CPT to examine pain-related outcomes in children ≤18 years old published after 2005 were identified, 2005 being when published pediatric CPT studies were last reviewed and guidelines for pediatric use of the CPT were published. Information related to samples, CPT methodology, and pain outcomes was recorded. Thirty-six published papers, involving 2,242 children (aged 3-18 years) from both healthy and clinical samples, met review inclusion criteria. Several aspects of CPT methodology with significant potential to impact pain outcomes were found to be inconsistently implemented and reported, including water temperature, use of informed versus uninformed ceilings, and the presence of observers during the CPT. Self-report child pain intensity and pain tolerance were common outcomes. A number of refinements for use of the CPT in pediatric pain research are suggested. ⋯ The cold pressor task is a commonly used experimental method in pediatric pain research. This systematic review reveals important methodological inconsistencies in its use and suggestions for improvements to previously published guidelines.
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The current study examined the Fear Avoidance (FA) model of chronic pain in pediatric chronic pain patients. Multiple structural equation models were tested in the current study with pairwise parameter comparisons made between younger children (8-12 years) and adolescents (13-17 years). Within a sample of 350 children and adolescents, we examined functional disability and depressive symptoms in separate models with the following predictor variables-pain, pain catastrophizing, fear of pain, and avoidance of activities-after controlling for duration of pain. For a subset of patients (n = 151), we also tested a brief prospective outcome model with baseline predictor variables and functional disability at 1-month follow-up. The FA models predicting functional disability concurrently and prospectively were an excellent fit to the data. The theorized FA model for depression was a poor fit. When the model was modified to include direct pathways from the cognitive processes of pain catastrophizing and fear of pain to depressive symptoms, the model fit was significantly improved. In the examination of developmental differences between younger children and adolescent patients, duration of pain contributed to the model for younger children, whereas pain-related fears were more influential for adolescent patients. ⋯ The FA model of chronic pain appears to be applicable for pediatric patients with some modification to account for developmental differences across childhood. We discuss the developmental, theoretical, and clinical implications of these results.
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The aim of this study was to assess the association of chronic pain with different lifestyle factors and psychological symptoms in a large, unselected adolescent population. Pain was evaluated as chronic non-specific pain, chronic multisite pain, and in additional analyses, chronic pain with high disability. The study was performed during 2006 to 2008 in Nord-Trøndelag County, Norway. Adolescents aged 13 to 18 years were invited to participate. The response rate was 78%. The final study population consisted of 7,373. Sedentary behavior and pain were associated only in girls. In both sexes, overweight and obesity were associated with increased odds of pain. Whereas both smoking and alcohol intoxication showed strong associations with pain, the associations were attenuated after adjustments for psychosocial factors. Symptoms of anxiety and depression showed the strongest associations with pain (odds ratio 4.1 in girls and 3.7 in boys). The odds of pain increased gradually by number of unfavorable lifestyle factors reported. This study revealed consistent associations between lifestyle factors, anxiety and depression, and chronic pain, including multisite pain and pain with high disability. The consistency across the different pain categories suggests common underlying explanatory mechanisms, and despite the cross-sectional design, the study indicates several modifiable targets in the management of adolescent chronic pain. ⋯ This study showed a clear and consistent relation between different lifestyle factors, anxiety and depression, and the pain categories chronic non-specific pain, multisite pain, and also pain with high disability. Independent of causality, it underlines the importance of a broad perspective when studying, preventing, and treating chronic pain in adolescents.
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Randomized Controlled Trial
Respiration-induced hypoalgesia: exploration of potential mechanisms.
Slow breathing is used as a means to reduce pain, yet the mechanisms responsible for respiration-induced hypoalgesia are poorly understood. The present study asked 30 healthy participants (M(age) = 21 years, M(education) = 15 years, 80% white non-Hispanic) to breathe at normal, slow (50% normal), and fast (125% normal) rates while constant-intensity, suprathreshold electric stimulations were delivered to the sural nerve to elicit pain and the nociceptive flexion reflex (NFR, a measure of spinal nociception). Stimulations were equally balanced across inhalations and exhalations to determine whether parasympathetic activation during exhalations contributes to hypoalgesia. Respiration rate, heart rate variability (HRV, a measure of parasympathetic activity), heart rate, and subjective arousal were assessed as manipulation checks. Slow breathing reduced pain relative to normal breathing and fast breathing, but NFR was not influenced by breathing. Further, pain and NFR did not differ between exhalations and inhalations, and changes in HRV did not correlate with changes in pain or NFR. Together, these findings suggest that respiration-induced hypoalgesia does not require gating of spinal nociception or changes in parasympathetic activity. ⋯ Slow breathing reduced pain relative to normal and fast breathing. This respiration-induced hypoalgesia does not appear to be due to gating of spinal nociception or changes in parasympathetic activity.