Articles: hyperalgesia.
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Identification of mechanisms for pain/hyperalgesia following spinal cord injury requires long-term evaluation of individual subjects because of the variability in effect over time for humans. ⋯ Histology revealed that hyperalgesia occurred when there was: (1) damage to spinal white matter; or (2) cystic cavitation; or (3) compression and distortion of the spinal cord without an obvious loss of grey or white matter.
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The neurobiological mechanisms underlying chronic pain associated with cancers are not well understood. It has been hypothesized that factors specifically elevated in the tumor microenvironment sensitize adjacent nociceptive afferents. We show that parathyroid hormone-related peptide (PTHrP), which is found at elevated levels in the tumor microenvironment of advanced breast and prostate cancers, is a critical modulator of sensory neurons. ⋯ We also observed an increase in plasma membrane TRPV1 protein levels after exposure to PTHrP, leading to upregulation in the proportion of TRPV1-responsive neurons, which was dependent on the activity of PKC and Src kinases. Furthermore, co-injection of PKC or Src inhibitors attenuated PTHrP-induced thermal but not mechanical hypersensitivity. Altogether, our results suggest that PTHrP and mild acidic conditions could induce constitutive pathological activation of sensory neurons through upregulation of TRPV1 function and trafficking, which could serve as a mechanism for peripheral sensitization of nociceptive afferents in the tumor microenvironment.
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The Journal of physiology · Sep 2015
Human psychophysics and rodent spinal neurones exhibit peripheral and central mechanisms of inflammatory pain in the UVB and UVB heat rekindling models.
Translational research is key to bridging the gaps between preclinical findings and the patients, and a translational model of inflammatory pain will ideally induce both peripheral and central sensitisation, more effectively mimicking clinical pathophysiology in some chronic inflammatory conditions. We conducted a parallel investigation of two models of inflammatory pain, using ultraviolet B (UVB) irradiation alone and UVB irradiation with heat rekindling. We used rodent electrophysiology and human quantitative sensory testing to characterise nociceptive processing in the peripheral and central nervous systems in both models. ⋯ Additional heat rekindling produces markers of central sensitisation in both species, including enhanced receptive field sizes. Importantly, we also showed a correlation in the evoked activity of rat spinal neurones to human thermal pain thresholds. The parallel results in rats and humans validate the translational use of both models and the potential for such models for preclinical assessment of prospective analgesics in inflammatory pain states.
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Long-term potentiation in the spinal dorsal horn requires peptidergic C-fibre activation in animals. Perceptual correlates of long-term potentiation following high-frequency electrical stimulation in humans include increased sensitivity to electrical stimuli at the high frequency stimulation site (homotopic pain-long-term potentiation) and increased sensitivity to pinprick surrounding the high frequency stimulation site (heterotopic pain-long-term potentiation, equivalent to secondary hyperalgaesia). To characterize the peripheral fibre populations involved in induction of pain-long-term potentiation, we performed two selective nerve block experiments in 30 healthy male volunteers. ⋯ Nociceptive afferents that induce pain amplification can be readily dissociated from those mediating pain. These findings add substantially to our understanding of the mechanisms of pain amplification, that form the basis for understanding the mechanisms of hyperalgesia encountered in patients. See Sandkühler (doi:10.1093/brain/awv193) for a scientific commentary on this article.
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Pulsed radiofrequency (PRF) treatment is a minimally invasive technique with multiple therapeutic applications. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel mediating Ih may regulate neuropathic pain signaling. This study aimed to determine whether PRF suppresses neuropathic pain by altering HCN channel expression in dorsal root ganglion (DRG) neurons. ⋯ The results showed that thermal hyperalgesia, mechano-allodynia, and mechano-hyperalgesia were lower, and DRG expression levels of HCN1 and HCN2 higher, in the PRF group compared with sham control animals (all P < 0.05 at D14). In conclusion, PRF can upregulate HCN channel expression in the DRG of rats with sciatic nerve CCI. How this regulation of Ih in nociceptive afferents contributes to the suppression of neuropathic pain by PRF remains to be determined.