Interleukin-10 (IL-10) is an anti-inflammatory cytokine that has been shown to play a role in inflammatory and autoimmune disorders as well as in neuropathic pain conditions. The objective of the present study was to assess the levels of IL-10 in rat's dorsal root ganglion (DRG) and the sciatic nerve following four different forms of sciatic nerve injury. The models used to induce the injury included two models of partial nerve injury: partial sciatic ligation (PSL) and chronic constriction injury (CCI), a model of complete sciatic transection (CST) and a model of perineural inflammation with minimal nerve damage (neuritis). Withdrawal responses for mechanical stimulus and withdrawal latency for thermal stimulation were used to measure mechanical and thermal hyperalgesia, respectively, and duration of the nociceptive withdrawal reflex to mechanical stimulus was used to measure mechanical hyperalgesia. The affected and contra-lateral nerves and the affected side DRG IL-10 levels were assessed by the means of enzyme-linked immunosorbent assay (ELISA), 3 and 8 days following the procedure and were compared to naïve rats' IL-10 levels. The rats exposed to CCI and neuritis developed significant mechanical and thermal hyperalgesia as well as mechanical hyperalgesia 3 and 8 days following the surgical procedure. Rats exposed to CST did not respond to mechanical stimulation and developed thermal hypoalgesia 3 and 8 days after the surgery. The DRG IL-10 levels were significantly reduced 3 and 8 days following CCI and PSL, significantly increased 3 and 8 days following CST, and remained unchanged following neuritis. The sciatic nerve IL-10 levels reduced significantly in both injured and contra-lateral nerves 3 and 8 days following CCI and PSL, elevated significantly in the injured but not in the contra-lateral nerve 3 and 8 days following CST and remained unchanged following neuritis. The results of this study suggest that IL-10's role in the neuropathic pain etiology may be specific to nerve injury type. Complete nerve transection increases while partial nerve injury reduces IL-10 levels in the involved nerve, and DRG. Perineural inflammation with minimal nerve damage has no effect on IL-10 levels.
We present novel sex-specific transcriptional regulation in trigeminal ganglia that may contribute to male-/female-based differences in trigeminal neuropathic pain. These findings are expected to open new research horizons, particularly in male versus female targeted therapeutic regimens.
Background
The dorsal root (DRG) and trigeminal (TG) ganglia contain cell bodies of sensory neurons of spinal and trigeminal systems, respectively. They are homologs of each other; however, differences in how the two systems respond to injury exist. Trigeminal nerve injuries rarely result in chronic neuropathic pain (NP). To date, no genes involved in the differential response to nerve injury between the two systems have been identified. We examined transcriptional changes involved in the development of trigeminal and spinal NP.
Methods
Trigeminal and spinal mononueropathies were induced by chronic constriction injury to the infraorbital or sciatic nerve. Expression levels of 84 genes in the TG and DRG at 4, 8 and 21 days post‐injury were measured using real‐time PCR.
Results
We found time‐dependent and ganglion‐specific transcriptional regulation that may contribute to the development of corresponding neuropathies. Among genes significantly regulated in both ganglia Cnr2, Grm5, Htr1a, Il10, Oprd1, Pdyn, Prok2 and Tacr1 were up‐regulated in the TG but down‐regulated in the DRG at 4 days post‐injury; at 21 days post‐injury, Adora1, Cd200, Comt, Maob, Mapk3, P2rx4, Ptger1, Tnf and Slc6a2 were significantly up‐regulated in the TG but down‐regulated in the DRG.
Conclusions
Our findings suggest that spinal and trigeminal neuropathies due to trauma are differentially regulated. Subtle but important differences between the two ganglia may affect NP development.
Significance
We present distinct transcriptional alterations in the TG and DRG that may contribute to differences observed in the corresponding mononeuropathies. Since the trigeminal system seems more resistant to developing NP following trauma our findings lay ground for future research to detect genes and pathways that may act in a protective or facilitatory manner. These may be novel and important therapeutic targets.
Interleukin-8 (IL-8) is a pro-inflammatory cytokine that has been shown to play a role in inflammatory and autoimmune disorders. The objective of the present study was to assess the levels of IL-8 in rat serum, dorsal root ganglion (DRG) and the sciatic nerve following four different forms of sciatic nerve injury. The models used to induce the injury included partial sciatic ligation (PSL), chronic constriction injury (CCI), perineural inflammation (neuritis) and complete sciatic transection (CST). Mechanical and thermal hyperalgesia were detected by measuring withdrawal responses from a mechanical stimulus and withdrawal latency from thermal stimulation. Enzyme-linked immunosorbent assays (ELISA) was used to assess the IL-8 levels in the affected and contralateral sciatic nerves. Rats exposed to PSL and neuritis developed significant nociceptive response (mechanical and thermal hyperalgesia) in the affected side at three days post-surgery whereas the CCI group at eight days post-surgery. No mechanical or thermal hyperalgesia was observed in rats exposed to CST at either three or eight days postsurgery. Additionally, IL-8 levels were significantly increased in the injured sciatic nerve at 3 and 8days following PSL and neuritis as well as at 8days following CCI when compared to naïve animals. A significant up regulation of IL-8 levels was observed in the ipsilateral DRG at 3 and 8days following CST compared to naïve animals. The serum IL-8 levels remained unchanged in all models of nerve damage. The results of this study suggest that IL-8's role in the neuropathic pain etiology may be specific to nerve injury type.
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