Pain
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The susceptibility of changes in responsiveness to noxious cold stimulation of rats submitted to chronic constriction of the infraorbital nerve (CION) or carrageenan to drug inhibition was compared. Nocifensive responses were measured as total time rats engaged in bilateral facial grooming with both forepaws over the first 2 min following tetrafluoroethane spray application to the snout. Carrageenan (50 microg, s.c. into upper lip) caused short-lived ipsilateral cold hyperalgesia (peak at 3 h: vehicle 8.4+/-1.3, carrageenan 21.2+/-3.0 s) which was markedly suppressed by i.p. indomethacin (4 mg/kg), celecoxib (10mg/kg) or s.c. dexamethasone (0.5 mg/kg), endothelin ET(A) or ET(B) receptor antagonists (BQ-123 and BQ-788, respectively; 10 nmol/lip). ⋯ Bosentan (dual ET(A)/ET(B) receptor antagonist, 10 mg/kg, i.v.) abolished CION-induced cold hyperalgesia for up to 6h. Thus, once established, CION-induced orofacial hyperalgesia to cold stimuli appears to lack an inflammatory component, but is alleviated by endothelin ET(A) and/or ET(B) receptor antagonists. If this CION injury model bears predictive value to trigeminal neuralgia (i.e., paroxysmal orofacial pain triggered by various stimuli), endothelin receptors might constitute new targets for treatment of this disorder.
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Important mechanisms that regulate inhibitory and facilitatory effects on TRPV1-mediated nociception are desensitization and phosphorylation, respectively. Using Ca2+-imaging, we have previously shown that desensitization of TRPV1 upon successive capsaicin applications was reversed by protein kinase C activation in dorsal root ganglion neurons and CHO cells. Here, using both Ca2+-imaging and patch-clamp methods, we show that PMA-induced activation of PKCepsilon is essential for increased sensitivity of desensitized TRPV1. ⋯ We also show that the expression level of PKCepsilon paralleled the amount of phosphorylated TRPV1 protein using an antibody specific for phosphorylated TRPV1 at S800. Furthermore, the anti-phosphoTRPV1 antibody detected phosphorylation of TRPV1 in mouse and rat DRG neurons and may be useful for research regarding nociception in native tissues. This study, therefore, identifies PKCepsilon and S800 as important therapeutic targets that may help regulate inhibitory effects on TRPV1 and hence its desensitization.
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Comparative Study
Quantitative sensory testing in children with migraine: preliminary evidence for enhanced sensitivity to painful stimuli especially in girls.
Recent studies showed an enhanced general sensitivity to painful stimuli in adult migraineurs during as well as between attacks. Yet, the influence of a prolonged pain history and potential sex differences has not been studied. We used quantitative sensory testing to examine 25 children with migraine between attacks and 28 controls (age 9-15). ⋯ To summarize, an enhanced sensitivity to painful stimuli can already be observed in children suffering from migraine for an average duration of 4.4 years. This may be the result of sensitization in nociceptive pain pathways caused by frequent pain experiences. Girls with migraine were more prone to such sensitization, which may increase their risk for continuing to suffer from migraine throughout adulthood.
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The aim of this study was to investigate involvement of central mechanisms in complex regional pain syndrome (CRPS). In particular, we wished to determine whether hyperalgesia extends ipsilaterally from the affected limb to the forehead. The heat-pain threshold, pressure-pain threshold, and ratings of cold and sharpness were investigated on each side of the forehead and in the affected and unaffected limbs of 38 patients with features of CRPS. ⋯ Although the heat-pain threshold and ratings of sharpness and cold did not differ between the two sides of the forehead in the group as a whole, the sharpness of pinprick sensations in the affected limb was mirrored by similar sensations in the ipsilateral forehead. Conversely, diminished sensitivity to light touch in the affected limb was associated with diminished sensitivity to sharpness, cold and heat-pain in the ipsilateral forehead. These findings suggest that central nociceptive processing is disrupted in CRPS, possibly due to disturbances in the thalamus or higher cortical centres.
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Neuroimaging methods have so far identified various structures in the brain involved in the processing of pain and its control. However, our understanding of their anatomical connectivities is relatively weak. ⋯ Group analysis showed that tract paths could be defined and their likelihood quantified for connections between the PAG and separately for the NCF, to the prefrontal cortex, amygdala, thalamus, hypothalamus and rostroventral medial medulla bilaterally. The connections identified confirm the existence of an anatomical circuitry for the functionally characterised top-down influences on pain processing via brainstem structures in humans.