Articles: hyperalgesia-pathology.
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Proc. Natl. Acad. Sci. U.S.A. · Nov 2009
Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia.
Transient receptor potential vanilloid 1 (TRPV1) plays a major role in hyperalgesia and allodynia and is expressed both in the peripheral and central nervous systems (CNS). However, few studies have evaluated mechanisms by which CNS TRPV1 mediates hyperalgesia and allodynia after injury. We hypothesized that activation of spinal cord systems releases endogenous TRPV1 agonists that evoke the development of mechanical allodynia by this receptor. ⋯ Finally, intrathecal neutralization of 9- and 13-HODE by antibodies blocks CFA-evoked mechanical allodynia. These data collectively reveal a mechanism by which an endogenous family of lipids activates TRPV1 in the spinal cord, leading to the development of inflammatory hyperalgesia. These findings may integrate many pain disorders and provide an approach for developing analgesic drugs.
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Pontospinal noradrenergic neurons form a component of an endogenous analgesic system and represent a potential therapeutic target. We tested the principle that genetic manipulation of their excitability can alter nociception using an adenoviral vector (AVV-PRS-hKir(2.1)) containing a catecholaminergic-selective promoter (PRS) to retrogradely transduce and inhibit the noradrenergic neurons projecting to the lumbar dorsal horn through the expression of a potassium channel (hKir(2.1)). Expression of hKir(2.1) in catecholaminergic PC12 cells hyperpolarized the membrane potential and produced a barium-sensitive inward rectification. ⋯ In the formalin test, rats transduced with hKir(2.1) showed enhanced nocifensive behaviors (both Phase I and II, p < 0.05, n = 11/group) and increased c-Fos-positive cells in the lumbar dorsal horn. Transduction with AVV-PRS-hKir(2.1) before spared nerve injury produced no change in tactile or cold allodynia. Thus, the selective genetic inhibition of approximately 150 pontospinal noradrenergic neurons produces a modality-specific thermal hyperalgesia, increased nocifensive behaviors, and spinal c-Fos expression in the formalin test, but not in the spared nerve injury model of neuropathic pain, indicating that these neurons exert a selective tonic restraining influence on in vivo nociception.
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Comparative Study
Spinal microglial expression and mechanical hypersensitivity in a postoperative pain model: comparison with a neuropathic pain model.
Postoperative pain control contributes to quality of life. Activation of spinal cord microglia after peripheral nerve injury contributes to mechanical hypersensitivity. The contribution of spinal cord microglia to hypersensitivity after surgery, however, is not well understood. Here, the authors evaluated whether inhibition of spinal microglia reduced postoperative mechanical hypersensitivity, and if so, whether the effect differed from that in a rat neuropathic pain model. ⋯ The results of the present study suggest that spinal OX42 expression has a more important role in the development of neuropathic pain than in postoperative pain, and that an increase in spinal OX42 expression does not contribute to postoperative mechanical hypersensitivity.
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In human conditions, chronic pain is associated with widespread anatomical changes in the brain. Nevertheless, little is known about the time course of these changes or the relationship of anatomical changes to perception and behaviour. In the present study, we use a rat model of neuropathic pain (spared nerve injury, SNI) and 7 T MRI to determine the longitudinal supraspinal changes associated with pain-like and anxiety-like behaviours. ⋯ There was also decreased volume in retrosplenial and entorhinal cortices. We also explored areas that correlated with mechanical hyperalgesia and found that increased hyperalgesia was associated with decreased volumes in bilateral S1 hindlimb area, anterior cingulate cortex (ACC, areas 32 and 24), and insula. Overall, our results suggest that long-term neuropathic pain has widespread effects on brain anatomy related to the duration and magnitude of the pain.
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Despite the clear roles played by peroxisome proliferators-activated receptor alpha (PPAR-alpha) in lipid metabolism, inflammation and feeding, the effects of its activation in the central nervous system (CNS) are largely unknown. Palmitoylethanolamide (PEA), a member of the fatty-acid ethanolamide family, acts peripherally as an endogenous PPAR-alpha agonist, exerting analgesic and anti-inflammatory effects. Both PPAR-alpha and PEA are present in the CNS, but the specific functions of this lipid and its receptor remain to be clarified. ⋯ To investigate the mechanism by which PEA attenuated hyperalgesia, we evaluated inhibitory kB-alpha (IkB-alpha) degradation and p65 nuclear factor kB (NF-kappaB) activation in DRG. PEA prevented IkB-alpha degradation and p65 NF-kappaB nuclear translocation, confirming the involvement of this transcriptional factor in the control of peripheral hyperalgesia. These results add further support to the broad-spectrum of biological and pharmacological effects induced by PPAR-alpha agonists, suggesting a centrally mediated component for these drugs in controlling inflammatory pain.