The journal of pain : official journal of the American Pain Society
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Spinally released brain-derived nerve growth factor (BDNF) after nerve injury is essential to anatomic and functional changes in spinal noradrenergic and cholinergic systems, which are engaged or targeted by commonly used treatments for neuropathic pain. Since BDNF signals via tropomyosine receptor kinases (trks), we tested whether trk blockade by repeated spinal injection of the trk inhibitor K252a would reduce anatomical (spinal noradrenergic and cholinergic fiber density), functional (α2-adrenoceptor-mediated direct stimulation of spinal cholinergic terminals), and behavioral (anti-hypersensitivity from systemic gabapentin and spinal clonidine) plasticity, which depends on BDNF. Spinal K252a treatment did not alter hypersensitivity from spinal nerve ligation (SNL), but blocked the SNL-associated increase in dopamine-β-hydroxylase (DβH) fiber density in the spinal cord dorsal horn while reducing spinal choline acetyltransferase (ChAT)-immunoreactivity. K252a treatment also abolished the facilitatory effect of dexmedetomidine on KCl-evoked acetylcholine release in spinal cord synaptosomes and reduced the anti-hypersensitivity effects of oral gabapentin and spinal clonidine. These results suggest that spinal trk signaling is essential for the anatomic and functional plasticity in noradrenergic and cholinergic systems after nerve injury and consequently for the analgesia from drugs that rely on these systems. ⋯ Many drugs approved for neuropathic pain engage spinal noradrenergic and cholinergic systems for analgesia. This study demonstrates that spinal trk signaling after nerve injury is important to neuroplasticity of these systems, which is critical for the analgesic action of common treatments for neuropathic pain.
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The expression of NF-κB in the spinal cord is associated with neuropathic pain. However, little is known about its expression beyond the spinal cord. Here we examined a spatial and temporal pattern of the NF-κB expression in both spinal and supraspinal regions. After chronic constriction injury (CCI) of the sciatic nerve, NF-κB (p65) expression was significantly increased in the ipsilateral spinal cord. In contrast, the NF-κB expression in the contralateral primary somatosensory cortex was decreased with no significant differences seen in the thalamus. In the contralateral anterior cingulate cortex, the NF-κB expression was increased significantly on day 14 as compared with the sham group. In the contralateral amygdala, the NF-κB expression showed a time-dependent downregulation after CCI, which became significant on day 14. MK-801 reduced nociceptive behaviors and reversed the direction of NF-κB expression. These results indicate that the CCI-induced expression of p65 NF-κB is both time-dependent and region-specific, in areas that process both sensory-discriminative and motivational-affective dimensions of pain. ⋯ This article presents a spatiotemporal mapping of the NF-κB expression in spinal and supraspinal regions after peripheral nerve injury. These findings point to an involvement of NF-κB beyond the spinal cord in both the sensory discriminative and emotional affective aspects of neuropathic pain processing.
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Evaluating pain in verbal children in the hospital setting is done primarily through serial assessments of pain intensity using single-item measures. However, little remains known about intensity scales' relative responsiveness and uniqueness from negative affect in this clinical setting. In the present study, a total of 411 assessments using 3 common pediatric pain intensity measures (the Faces Pain Scale-Revised, a verbally presented numeric rating scale, and a visual analog scale) were obtained over a period of 3 days from 29 children ages 9 to 18 years following a relatively standardized surgical procedure. Hierarchical linear models were used to compare the 3 scales on responsiveness over postoperative recovery time, invariance across baseline variables (age, sex, and baseline mood), and distinctiveness from changes in negative affect. Results showed that all 3 pain-intensity measures were highly interrelated, varied similarly with age and baseline state anxiety, and were comparably related to contemporaneous changes in affect. However, patients tended to rate pain intensity higher on the Numerical Rating Scale, and only this scale failed to reflect a decreasing trend in pain scores with elapsed surgical recovery time. Potential implications for clinical practice are discussed. ⋯ This article presents data comparing the responsiveness over time and association with negative affect of 3 single-item pediatric pain-intensity scales commonly used in hospital settings. The results can help inform the selection of self-report measures when serially evaluating pain and treatment response in hospitalized children.
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Because fibromyalgia (FM) patients frequently report activity-dependent deep tissue pains, impulse input from painful body regions may be relevant for their musculoskeletal complaints. In addition, peripheral impulse input may induce and maintain thermal and mechanical hyperalgesia of FM patients. If so, activity and rest may alternately enhance and diminish intensity of FM pain. However, the effects of exercise on pain are ambiguous in studies of FM. Whereas exercise-only studies demonstrated increased pain and hyperalgesia during and after physical activity, some exercise studies that included rest periods resulted in decreased FM pain and increased function. To further clarify these effects, we examined the effects of alternating exercise with rest on clinical pain and thermal/mechanical hyperalgesia of 34 FM patients and 36 age-matched healthy controls (NC). Using an ergometer, all subjects performed arm exercise to exhaustion twice alternating with 15-minute rest periods. Although strenuous muscle activity was reported as painful by most FM subjects, overall clinical pain consistently decreased during the rest periods. Additionally, FM subjects' pain sensitivity to mechanical pressure decreased after each exercise and rest session. ⋯ FM is a pain-amplification syndrome that depends at least in part on peripheral tissue impulse input. Whereas muscle activity increased overall pain, short rest periods produced analgesic effects.
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The endocannabinoids anandamide and 2-arachidonoylglycerol are predominantly regulated by the respective catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Inhibition of these enzymes elevates endocannabinoid levels and attenuates neuropathic pain. In the present study, CB₁ and CB₂ receptor-deficient mice were subjected to chronic constriction injury (CCI) of the sciatic nerve to examine the relative contribution of each receptor for the anti-allodynic effects of the FAAH inhibitor, PF-3845, and the MAGL inhibitor, JZL184. CCI caused marked hypersensitivity to mechanical and cold stimuli, which was not altered by deletion of either the CB₁ or CB₂ receptor, but was attenuated by gabapentin, as well as by each enzyme inhibitor. Whereas PF-3845 lacked anti-allodynic efficacy in both knockout lines, JZL184 did not produce anti-allodynic effects in CB₁ (-/-) mice, but retained its anti-allodynic effects in CB₂ (-/-) mice. These data indicate that FAAH and MAGL inhibitors reduce nerve injury-related hyperalgesic states through distinct cannabinoid receptor mechanisms of action. In conclusion, although endogenous cannabinoids do not appear to play a tonic role in long-term expression of neuropathic pain states, both FAAH and MAGL represent potential therapeutic targets for the development of pharmacological agents to treat chronic pain resulting from nerve injury. ⋯ This article presents data addressing the cannabinoid receptor mechanisms underlying the anti-allodynic actions of endocannabinoid catabolic enzyme inhibitors in the mouse sciatic nerve ligation model. Fatty acid amide hydrolase and monoacylglycerol lipase inhibitors reduced allodynia through distinct cannabinoid receptor mechanisms. These enzymes offer potential targets to treat neuropathic pain.