Pain
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For most healthy subjects, both subjective pain ratings and pain-evoked potentials are attenuated under conditioned pain modulation (CPM; formerly termed diffuse noxious inhibitory controls, or DNIC). Although essentially spinal-bulbar, this inhibition is under cortical control. This is the first study to observe temporal as well as spatial changes in cortical activations under CPM. ⋯ This was followed by reduced activations in the primary and secondary somatosensory cortices, supplementary motor area, posterior insula, and anterior cingulate cortex from 400 ms poststimulus. Our findings show that the prefrontal pain-controlling areas of OFC and amygdala increase their activity in parallel with subjective pain reduction under CPM, and that this increased activity occurs prior to reductions in activations of the pain sensory areas. In conclusion, achieving pain inhibition by the CPM process seems to be under control of the OFC and the amygdala.
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Transient receptor potential ion channel melastatin subtype 8 (TRPM8) is activated by cold temperatures and cooling agents, such as menthol and icilin. Compounds containing peppermint are reported to reduce symptoms of bowel hypersensitivity; however, the underlying mechanisms of action are unclear. Here we determined the role of TRPM8 in colonic sensory pathways. ⋯ Icilin also prevented mechanosensory desensitization and sensitization induced by capsaicin and the TRPA1 agonist AITC (40 μmol/L), respectively. TRPM8 is present on a select population of colonic high threshold sensory neurons, which may also co-express TRPV1. TRPM8 couples to TRPV1 and TRPA1 to inhibit their downstream chemosensory and mechanosensory actions.
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The present study examined whether a moderately aversive abdominal threat would lead to greater enhancement in affect- and pain-related defensive responding as indexed by the acoustic startle reflex (ASR) and nociceptive flexion reflex (NFR) in women compared to men. We also predicted sex differences in threat-related autonomic arousal measured by skin conductance responses (SCRs) to acoustic startle and noxious sural nerve stimulation. Unpredictable threat was manipulated by alternating 30-second safe ("no abdominal stimulation will be given") and threat ("abdominal stimulation may occur at anytime") periods. ⋯ Females also showed greater threat-potentiated SCRs to sural nerve stimulation than males. Our findings indicate that both affect- and pain-related defense and arousal systems are strongly influenced by threat of an aversive, unpredictable event, a situation associated with anticipatory anxiety. Females, compared to males, showed greater nociceptive responding and pain modulation when exposed to an unpredictable threatening context, whereas affect-driven ASR responses showed no such sex differentiation.
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Epinephrine (EPI) contributes to hyperalgesia in inflammatory and stress conditions. EPI signals via adrenoceptors, which are regulated by G protein-coupled receptor kinase 2 (GRK2). We previously reported that GRK2 is decreased in nociceptors during chronic inflammation. ⋯ In terms of EPI signalling pathways, the protein kinase A (PKA) inhibitor H-89 inhibited EPI-induced mechanical hyperalgesia in wild-type mice, whereas H-89 had no effect in mice with low GRK2 in sensory neurons (SNS-GRK2(+/-) mice). Conversely, intraplantar injection of the protein kinase Cε PKCε inhibitor TAT-PKC(εv1-2) inhibited hyperalgesia in sensory neuron specific (SNS)-GRK2(+/-) mice and not in wild-type mice. These results indicate that low GRK2 in primary sensory neurons switches EPI-induced signalling from a protein kinase A-dependent toward a PKCε-dependent pathway that ultimately mediates prolonged EPI-induced hyperalgesia.