Articles: hyperalgesia.
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Neuroscience letters · Jul 2017
Chronic exposure to tumor necrosis factor in vivo induces hyperalgesia, upregulates sodium channel gene expression and alters the cellular electrophysiology of dorsal root ganglion neurons.
The goal of these studies was to investigate the links between chronic exposure to the pro-inflammatory cytokine tumor necrosis factor (TNF), hyperalgesia and the excitability of dorsal root ganglion (DRG) sensory neurons. We employed transgenic mice that constitutively express TNF (TNFtg mice), a well-established model of chronic systemic inflammation. At 6 months of age, TNFtg mice demonstrated increased sensitivity to both mechanical and thermal heat stimulation relative to aged-matched wild-type controls. ⋯ Increased overlap of activation and inactivation in the TNFtg neurons produces inward Na+ currents at voltages near the resting membrane potential of sensory neurons (i.e. window currents). The combination of increased Na+ current amplitude, hyperpolarized shifts in Na+ channel activation and increased window current predicts a reduction in the action potential threshold and increased firing of small-diameter DRG neurons. Together, these data suggest that increases in the expression of Nav1.8 channels, regulatory β1 subunits and TNFR1 contribute to increased nociceptor excitability and hyperalgesia in the TNFtg mice.
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Changes in gene transcription in the dorsal root ganglion (DRG) after nerve trauma contribute to the genesis of neuropathic pain. We report that peripheral nerve trauma caused by chronic constriction injury (CCI) increased the abundance of the transcription factor C/EBPβ (CCAAT/enhancer binding protein β) in the DRG. Blocking this increase mitigated the development and maintenance of CCI-induced mechanical, thermal, and cold pain hypersensitivities without affecting basal responses to acute pain and locomotor activity. ⋯ These effects required C/EPBβ-mediated transcriptional activation of Ehmt2 (euchromatic histone-lysine N-methyltransferase 2), which encodes G9a, an epigenetic silencer of the genes encoding Kv1.2 and MOR. Blocking the increase in C/EBPβ in the DRG improved morphine analgesia after CCI. These results suggest that C/EBPβ is an endogenous initiator of neuropathic pain and could be a potential target for the prevention and treatment of this disorder.
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C fibers display activity-dependent slowing (ADS), whereby repetitive stimulation (≥1 Hz) results in a progressive slowing of action potential conduction velocity, which manifests as a progressive increase in response latency. However, the impact of ADS on spinal pain processing has not been explored, nor whether ADS is altered in inflammatory pain conditions. To investigate, compound action potentials were made, from dorsal roots isolated from rats with or without complete Freund's adjuvant (CFA) hindpaw inflammation, in response to electrical stimulus trains. ⋯ We also demonstrate a progressive delay of C fiber monosynaptic transmission to the spinal cord that is similarly sex and inflammation dependent. Experimentally manipulating ADS strongly influences spinal summation consistent with sex differences in behavioral pain thresholds. This suggests that ADS provides a peripheral mechanism that can regulate spinal nociceptive processing and pain sensation.
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Thoracotomy results in chronic postoperative pain (CPTP) in half of the cases. Earlier findings in rat models of persistent post-surgical pain suggest that spinal pathways are critical for pain onset but not its maintenance. Descending systems from the brain stem modulate nociceptive transmission in the spinal cord and contribute to persistent pain, but their role in chronic postoperative pain has not been studied. ⋯ SSP-SAP given at postoperative day 10 was equally effective in ablating NK-1R neurons but fully reversed mechano-hypersensitivity in only 3 of 9 hypersensitive rats. Fewer rats showed intense pain-like behavior, by Qualitative Hyperalgesia Profile analysis, in the Prevention than in the Control conditions, and the more intense pain behaviors declined along with SSP-SAP-induced Reversal of hypersensitivity. Neurokinin-1 receptor-expressing neurons in RVM appear essential for the development but contribute only partially to the maintenance of CPTP.