The journal of pain : official journal of the American Pain Society
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The central nucleus of the amygdala (CeA) is involved in processing and regulation of pain. We determined whether amygdaloid corticotropin-releasing factor (CRF) contributes to pain modulation in the neuropathic rat. Emotional aspect of pain was assessed by an aversive place-conditioning test and sensory aspect of pain by determining monofilament-induced limb-withdrawal threshold. CRF₆₋₃₃ (an inhibitor of CRF-binding protein) or CRF₉₋₄₁, a nonselective CRF receptor antagonist, was microinjected to the left or right CeA or a control site in rats with spared nerve injury (SNI) or sham operation of the left hind limb. In SNI animals, CRF₆₋₃₃ in the left or right CeA, but not in a control site, attenuated emotional painlike behavior and increased sensory pain. In sham controls, CRF₆₋₃₃ in the right but not left CeA increased sensory aspect of pain, without influence on place-avoidance behavior. The effects induced by CRF₆₋₃₃ were reversed by CRF₉₋₄₁. The results indicate that endogenous CRF in the CeA, through action on CRF receptors, may differentially influence emotional and sensory aspects of pain in neuropathy. While the right CeA had a dominant role in modulation of pain-related responses in sham controls, left as well as right CeA contributed to pain modulation in neuropathic animals. ⋯ An increase in free endogenous corticotropin-releasing factor in the central nucleus of the amygdala was accompanied by increased cutaneous hypersensitivity and decreased emotional painlike behavior in neuropathic animals. This finding indicates that CRF in the amygdala may have differential effects on sensory and emotional aspects of neuropathic pain.
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Central sensitization is one form of long-term plasticity in the central nervous system. Sustained activation of primary sensory fibers supplying dorsal horn can induce long-lasting increases in the discharge amplitude of primary afferent synapses. This is similar to the long-term potentiation that occurs in many other CNS regions. Drugs that limit the short-duration wind-up component of central sensitization include sodium channel blockers, NMDA antagonists, fast-acting opioids and the calcium-channel ligands gabapentin and pregabalin (S-3-(aminomethyl)-5-methylhexanoic acid). Pregabalin, like gabapentin, binds selectively to the Ca(V)α₂δ auxiliary subunit of presynaptic voltage-gated calcium channels. The conformational changes induced by this binding inhibit abnormally intense neuronal activity by reducing the synaptic release of glutamate and other neurotransmitters. Recent identification in animal models of increased Ca(V)α₂δ protein expression in chronic pain, allodynia, and hyperalgesia have drawn additional interest to drugs that bind the Ca(V)α₂δ site. Experimental studies with animal models and healthy human volunteers have shown that pregabalin reduces nociceptive responses, particularly in conditions involving central sensitization. Since these actions occur with relatively modest effects on physiological and cognitive functions, pregabalin may be an important consideration in the pharmacotherapy of otherwise difficult-to-treat pain syndromes. ⋯ This focus article discusses how the central nervous system plasticity phenomenon, central sensitization, is established in the induction and maintenance of chronic pain, allodynia, and hyperalgesia. In addition, it explores the neurophysiologic actions of the calcium-channel ligands gabapentin and pregabalin in limiting pathological manifestations of central sensitization.
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Emerging evidence suggests that some individuals with regional pain disorders go on to develop chronic widespread pain (CWP). However, the mechanism behind this transition and the nature of risk factors that predispose a person to develop CWP remain to be elucidated. The purpose of this study was to describe the frequency with which participants with chronic back or neck pain develop CWP and to determine the risk factors associated with this development. In a sample of 512 individuals, we found that nearly a quarter (22.6%) of subjects who presented with regional back or neck pain in 2001/2002 had developed CWP by 2007. Logistic regression indicated that 7 factors were associated with the transition to CWP: moderate or severe pain intensity, female gender, history of abuse, family history of CWP, severe interference with general activity, having 1 or more central sensitivity syndromes, and using more pain management strategies. History of abuse was not significant in multivariate analysis. Notably, number of depressive symptoms endorsed, pain duration, age, body mass index, number of medication classes used, and receipt of disability benefits were not significantly associated with this transition. ⋯ This study offers insight into risk factors associated with the development of CWP. This information not only offers clues as to the mechanism behind the expansion of pain sensitivity from a regional pain locus to a widespread pain disorder but also provides insight as to how clinicians might mitigate this transition.
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Sex differences in the processing and experience of emotion exist. The present study examined whether sex differences in emotion lead to sex differences in affective modulation of pain and spinal nociception (assessed by nociceptive flexion reflex, NFR). Participants were healthy men (n = 47) and women (n = 73). Prior to affective modulation testing, electrocutaneous pain sensitivity was assessed (NFR threshold, pain threshold, pain tolerance). Affective modulation of pain and NFR was then assessed by presenting pictures that vary in emotional valence and arousal (mutilation, attack, death, neutral, families, adventure, erotica) during which suprathreshold electrocutaneous stimulations were delivered. Subjective emotional reactions were assessed after every picture, and nociceptive reactions were assessed after every suprathreshold stimulus. Results indicated women had greater pain sensitivity and also responded more negatively to attack pictures and less positively to erotic pictures. But despite these differences, affective modulation of pain/NFR was not moderated by sex: erotic pictures inhibited pain/NFR and mutilation pictures enhanced pain/NFR. Together, this implies subjective emotional experience does not completely mediate picture-evoked modulation of pain/NFR, a supposition that was further supported by exploratory analyses that demonstrated picture-evoked modulation of pain/NFR was present even after controlling for intra- and inter-individual differences in emotional reactions to pictures. Implications and limitations of these findings are discussed. ⋯ Evidence suggests that women are more sensitive to experimental and clinical pain, but the mechanisms contributing to these sex differences are poorly understood. Affective processes are known to play a role in regulating pain signaling and pain experience; therefore, the present study examined whether sex differences in affective experience contribute to sex differences in pain. Results indicate that in healthy individuals affective processes may not contribute to sex differences in pain.
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Few data have been available on the functional role of small fiber damage in patients with peripheral nerve injuries with and without spontaneous pain. The aim of the present study was to investigate the function of large myelinated nerve fibers as well as small nerve fibers in a material of 60 patients with peripheral nerve injuries in upper or lower extremities, 30 patients with spontaneous pain, and 30 patients without pain. Patients were questioned about the characteristics of pain and investigated clinically with EMG/neurography and assessment of thermal thresholds in the innervation territory of the lesioned nerve as well as in the contralateral area. Sensation of touch and warmth and cold detection was significantly reduced in the injured side in both groups. There was a tendency, not significant, for heat pain thresholds to be more elevated in the affected side compared with the healthy side in the pain group only (47.8°C versus 45.1°C). There were no significant differences in thermal thresholds between the 2 groups of patients. The main finding was a high percentage of hyperphenomena (allodynia to light touch and reduced mechanical pain thresholds) in the pain group only. ⋯ Small fiber function did not significantly differ between patients with and without pain, indicating that elevated thermal thresholds alone will not reflect mechanisms responsible for the generation of pain. Hyperphenomena were present in the affected side of the pain group only.