The Journal of neuroscience : the official journal of the Society for Neuroscience
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Nicotine stimulates the activity of mesolimbic dopamine neurons, which is believed to mediate the rewarding and addictive properties of tobacco use. Accumulating evidence suggests that the endocannabinoid system might play a major role in neuronal mechanisms underlying the rewarding properties of drugs of abuse, including nicotine. Here, we investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area with electrophysiological techniques in vivo and in vitro. ⋯ They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-alpha triggered a nongenomic stimulation of tyrosine kinases, which might lead to phosphorylation and negative regulation of neuronal nicotinic acetylcholine receptors. These data indicate for the first time that the anorexic lipids OEA and PEA possess neuromodulatory properties as endogenous ligands of PPAR-alpha in the brain and provide a potential new target for the treatment of nicotine addiction.
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The ability to sense changes in the environment is essential for survival because it permits responses such as withdrawal from noxious stimuli and regulation of body temperature. Keratinocytes, which occupy much of the skin epidermis, are situated at the interface between the external environment and the body's internal milieu, and have long been appreciated for their barrier function against external insults. The recent discovery of temperature-sensitive transient receptor potential vanilloid (TRPV) ion channels in keratinocytes has raised the possibility that these cells also actively participate in acute temperature and pain sensation. ⋯ Upon selective pharmacological inhibition of TRPV1 with JNJ-17203212 [corrected], however, the keratinocyte-specific TRPV3 transgenic mice showed increased escape responses to noxious heat relative to their wild-type littermates. Coadministration of the cyclooxygenase inhibitor, ibuprofen, with the TRPV1 antagonist decreased inflammatory thermal hyperalgesia in transgenic but not wild-type animals. Our results reveal a previously undescribed mechanism for keratinocyte participation in thermal pain transduction through keratinocyte TRPV3 ion channels and the intercellular messenger PGE(2).
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Previous studies suggest that nocebo effects, sometimes termed "negative placebo effects," can contribute appreciably to a variety of medical symptoms and adverse events in clinical trials and medical care. In this study, using a within-subject design, we combined functional magnetic resonance imaging (fMRI) and an expectation/conditioning manipulation model to investigate the neural substrates of nocebo hyperalgesia using heat pain on the right forearm. ⋯ Functional connectivity analysis of spontaneous resting-state fMRI data from the same cohort of subjects showed a correlation between two seed regions (left frontal operculum and hippocampus) and pain network including bilateral insula, operculum, ACC, and left S1/M1. In conclusion, we found evidence that nocebo hyperalgesia may be predominantly produced through an affective-cognitive pain pathway (medial pain system), and the left hippocampus may play an important role in this process.
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Localized increases in synaptic strength constitute a synaptic basis for learning and memory in the CNS and may also contribute to the maintenance of neuropathic pain after spinal cord injury (SCI) through the de novo formation or elaboration of postsynaptic dendritic structures. To determine whether SCI-induced dendritic spine remodeling contributes to neuronal hyperexcitability and neuropathic pain, we analyzed spine morphometry, localization, and functional influence in dorsal horn (DH) neurons in adult rats 1 month after sham surgery, contusion SCI, and SCI treated with a selective inhibitor of Rac1 activation, NSC23766. After SCI, DH neurons located in lamina IV-V exhibited increased spine density, redistributed spines, and mature spines compared with control neurons, which was associated with enhancement of EPSCs in computer simulations and hyperexcitable responsiveness to innocuous and noxious peripheral stimuli in unit recordings in vivo. ⋯ Inhibition of the small GTP-binding protein Rac1 ameliorated post-SCI changes in spine morphology, attenuated injury-induced hyperexcitability of wide-dynamic range neurons, and progressively increased pain thresholds over a 3 d period. This suggests that Rac1 is an important intracellular signaling molecule involved in a spinal dendritic spine pathology associated with chronic neuropathic pain after SCI. Our report provides robust evidence for a novel conceptual bridge between learning and memory on the one hand, and neuropathic pain on the other.