Pain
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Rheumatoid arthritis (RA) is a chronic autoimmune arthritis that affects approximately 1% of the population. Synovial inflammation cannot fully explain the level of pain reported by patients and facilitation of pain processing at the spinal level has been implicated. We characterized the K/BxN serum transfer arthritis model as a model of joint inflammation-induced pain and examined pharmacologic responsiveness and spinal glia activation. ⋯ ATF3, a marker of nerve injury, was significantly increased in the lumbar dorsal root ganglia during the late phase (day 28). Hence, serum transfer in the K/BxN serum transfer arthritis model produces a persistent pain state, where the allodynia during the inflammatory state is attenuated by TNF and prostaglandin inhibitors, and the pharmacology and histochemistry data suggest a transition from an inflammatory state to a state that resembles a neuropathic condition over time. Therefore, the K/BxN serum transfer model represents a multifaceted model for studies exploring pain mechanisms in conditions of joint inflammation and may serve as a platform for exploring novel treatment strategies for pain in human arthritic conditions.
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Lamina II contains a large number of interneurons involved in modulation and transmission of somatosensory (including nociceptive) information. However, its neuronal circuitry is poorly understood due to the difficulty of identifying functional populations of interneurons. This information is important for understanding nociceptive processing and for identifying changes that underlie chronic pain. ⋯ Although noradrenaline and serotonin evoked outward currents in both inhibitory and excitatory cells, somatostatin produced these currents only in inhibitory neurons, suggesting that its pro-nociceptive effects are mediated by disinhibition. Our results demonstrate that certain distinctive populations of inhibitory and excitatory interneuron can be recognised in lamina II. Combining this approach with identification of other neurochemical markers should allow further clarification of neuronal circuitry in the superficial dorsal horn.
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Inflammation or pain during neonatal development can result in long-term structural and functional alterations of nociceptive pathways, ultimately altering pain perception in adulthood. We have developed a mouse model of neonatal colon irritation (NCI) to investigate the plasticity of pain processing within the viscerosensory system. Mouse pups received an intracolonic administration of 2% mustard oil (MO) on postnatal days 8 and 10. ⋯ Adult NCI mice displayed significant visceral hypersensitivity, as well as increased sensitivity to mechanical stimulation of the hindpaw, compared to control mice. The percentage of TRPA1-expressing colon afferents was significantly increased in NCI mice, however they displayed no increase in the percentage of TRPV1-immunopositive or capsaicin-sensitive colon DRG neurons. These results suggest that early neonatal colon injury results in a long-lasting visceral hypersensitivity, possibly driven by an early increase in growth factor expression and maintained by permanent changes in TRPA1 function.
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TNF-α contributes to up-regulation of Nav1.3 and Nav1.8 in DRG neurons following motor fiber injury.
A large body of evidence has demonstrated that the ectopic discharges of action potentials in primary afferents, resulted from the abnormal expression of voltage gated sodium channels (VGSCs) in dorsal root ganglion (DRG) neurons following peripheral nerve injury are important for the development of neuropathic pain. However, how nerve injury affects the expression of VGSCs is largely unknown. Here, we reported that selective injury of motor fibers by L5 ventral root transection (L5-VRT) up-regulated Nav1.3 and Nav1.8 at both mRNA and protein level and increased current densities of TTX-S and TTX-R channels in DRG neurons, suggesting that nerve injury may up-regulate functional VGSCs in sensory neurons indirectly. ⋯ Furthermore, inhibition of TNF-α synthesis, which prevented neuropathic pain, strongly inhibited the up-regulation of Nav1.3 and Nav1.8. The up-regulation of the both channels following L5-VRT was significantly lower in TNF receptor 1 knockout mice than that in wild type mice. These data suggest that increased TNF-α may be responsible for up-regulation of Nav1.3 and Nav1.8 in uninjured DRG neurons following nerve injury.
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We recently developed a rodent model of the painful muscle disorders induced by occupational exposure to vibration. In the present study we used this model to evaluate the function of sensory neurons innervating the vibration-exposed gastrocnemius muscle. Activity of 74 vibration-exposed and 40 control nociceptors, with mechanical receptive fields in the gastrocnemius muscle, were recorded. ⋯ While these high-firing nociceptors had lower mechanical thresholds than the remaining nociceptors, exposure to vibration had no effect on conduction velocity and did not induce spontaneous activity. Hyperactivity was not observed in any of 19 neurons from vibration-exposed rats pretreated with intrathecal antisense for the IL-6 receptor subunit gp130. Since vibration can injure peripheral nerves and IL-6 has been implicated in painful peripheral neuropathies, we suggest that the dramatic change in sensory neuron function and development of muscles pain, induced by exposure to vibration, reflects a neuropathic muscle pain syndrome.