Pain
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Emerging evidence supports an important role of posterior parasylvian areas in both pain and touch processing. Whether there are separate or shared networks for these sensations remains controversial. The present study compared spatial patterns of brain activation in response to unilateral nociceptive heat (47.5°C) or innocuous tactile stimulation (8-Hz vibration) to digits through high-resolution functional magnetic resonance imaging (fMRI) in squirrel monkeys. ⋯ Single voxels within each activation cluster showed robust BOLD signal changes during each block of nociceptive stimulation. Across animals (n=11), nociceptive response magnitudes of contralateral VS and pIns and ipsilateral Ri were significantly greater than corresponding areas in the opposite hemisphere. In sum, both distinct and shared areas in regions surrounding the posterior sylvian fissure were activated in response to nociceptive and tactile inputs in nonhuman primates.
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Peripheral injury or inflammation leads to a release of mediators capable of binding to a variety of ion channels and receptors. Among these are the 7-transmembrane receptors (G protein-coupled receptors) coupling to G(s), G(i/o), G₁₂/₁₃, or G(q/11) G proteins. Each of the G protein-coupled receptor pathways is involved in nociceptive modulation and pain processing, but the relative contribution of individual signaling pathways in vivo has not yet been worked out. ⋯ Surprisingly, our behavioral and electrophysiological experiments also indicated defects in basal mechanical sensitivity in G(q/11) mutant mice, suggesting a novel function for G(q/11) in tonic modulation of acute nociception. Patch-clamp recordings revealed changes in voltage-dependent tetrodotoxin-resistant and tetrodotoxin-sensitive sodium channels in nociceptors upon a loss of G(q/11), whereas potassium currents remained unchanged. Our results indicate that the functional role of the G(q)/G₁₁ branch of G-protein signaling in nociceptors in vivo not only spans sensitization mechanisms in pathological pain states, but is also operational in tonic modulation of basal nociception and acute pain.
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The L5 spinal nerve ligation (SNL) is a widely used animal neuropathic pain model. There are conflicting reports regarding the extent of injury to the L4 dorsal root ganglion (DRG) neurons in this model. If a significant number of these neurons were injured, the previously reported phenotypic and electrophysiological changes at this level are in need of re-evaluation by separating the injured neurons and the frankly spared ones. ⋯ Comparison between ATF3+ and ATF3- neurons in the SNL L4 DRG revealed that (1) whereas NPY induction occurred in ATF3+ cells, BDNF increased mainly in ATF3- neurons; (2) although ATF3+ neurons had higher Nav1.3 signals than ATF3- neurons, these signals were much lower than those of the L5 DRG neurons; and (3) ATF3+/N52- neurons selectively lost Nav1.8 and Nav1.9 mRNAs. Comparison of the total neuronal populations among naïve, SNL, and sham-operated rats revealed no significant differences for all examined Nav mRNAs. Because neuropathic pain behaviors were developed by rats with SNL but not the sham-operation, the small number of injured L4 neurons likely do not contribute to the pathomechanisms of neuropathic pain.
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Impairment of spinal GABAergic inhibition is demonstrated to contribute to pathologic chronic pain states. We investigated spinal and peripheral GABAergic regulation of incisional pain in rats. We found that intrathecal but not peripheral administration of muscimol (GABA-A receptor agonist) and baclofen (GABA-B receptor agonist) reduced mechanical and thermal hyperalgesia after plantar incision in rats. ⋯ However, expression of GABA-A receptor subunits α2 and α3 and GABA-B receptor subunits within the dorsal horn of the spinal cord were unchanged after incision, indicating that receptor expression cannot explain a possible modulation of GABAergic inhibition after incision. Thus, other mechanisms need to be considered. In conclusion, GABA-A and GABA-B receptors are promising targets for postoperative, incisional pain in humans.