Activation of ERK/CREB pathway in spinal cord contributes to chronic constrictive injury-induced neuropathic pain in rats1

Abstract

Aim: To investigate whether activation and translocation of extracellular signalregulated kinase (ERK) is involved in the induction and maintenance of neuropathic pain, and effects of activation and translocation of ERK on expression of pCREB and Fos in the chronic neuropathic pain. Methods: Lumbar intrathecal catheters were chronically implanted in male Sprague-Dawley rats. The left sciatic nerve was loosely ligated proximal to the sciatica's trifurcation at approximately 1.0 mm intervals with 4-0 silk sutures. The mitogen-activated protein kinase kinase (MEK) inhibitor U0126 or phosphorothioate-modified antisense oligonucleotides (ODN) were intrathecally administered every 12 h, 1 d pre-chronic constriction injury (CCI) and 3 d post-CCI. Thermal and mechanical nociceptive thresholds were assessed with the paw withdrawal latency (PWL) to radiant heat and von Frey filaments. The expression of pERK, pCREB, and Fos were assessed by both Western blotting and immunohistochemical analysis. Results: Intrathecal injection of U0126 or ERK antisense ODN significantly attenuated CCI-induced mechanical allodynia and thermal hyperalgesia. CCI significantly increased the expression of p-ERK-IR neurons in the ipsilateral spinal dorsal horn to injury, not in the contralateral spinal dorsal horn. The time courses of pERK expression showed that the levels of both cytosol and nuclear pERK, but not total ERK, were increased at all points after CCI and reached a peak level on postoperative d 5. CCI also significantly increased the expression of pCREB and Fos. Phospho-CREBpositive neurons were distributed in all laminae of the bilateral spinal cord and Fos was expressed in laminae I and II of the ipsilateral spinal dorsal horn. Intrathecal injection of U0126 or ERK antisense ODN markedly suppressed the increase of CCI-induced pERK, pCREB and c-Fos expression in the spinal cord. Conclusion: The activation of ERK pathways contributes to neuropathic pain in CCI rats, and the function of pERK may partly be accomplished via the cAMP response element binding protein (CREB)-dependent gene expression.

Supraspinal role of protein kinase C in oxaliplatin-induced neuropathy in rat

“…In our experiments, Western blot protein level detection of ERK, SAPK/JNK and p38MAPK was unmodified with respect to control in thalamus, PAG and cortex from chronic oxaliplatin rats. Phosphorylation level of these molecules decreased in thalamus for ERK and SAPK/JNK and in PAG and striatum for ERK whereas increased consistently in cortex and striatum for SAPK/JNK and mildly for ERK in spinal cord as previously shown in other kinds of neuropathic pain [4,6,18]. A dramatic increase in p38MAPK phosphorylated form could be observed in thalamus and PAG.…”

Knockdown of L Calcium Channel Subtypes: Differential Effects in Neuropathic Pain

“…As in other models of neuropathy (Ma and Quirion, 2001;Miletic et al, 2002;Song et al, 2005;Crown et al, 2006), the expression of the phosphorylated form of the CREB transcription factor significantly increased in the ipsilateral dorsal horn of SNL animals (Fig. 9, SNL, black bars), both in superficial and deep laminae (respectively ϩ21.0 Ϯ 2.8% and ϩ21.4 Ϯ 2.0% compared to contralateral dorsal horn).…”

“…Pathological changes in neuronal sensitization associated with chronic pain, involve such multiple gene regulation following neuronal hyperactivity (Woolf and Salter, 2000), and activation of the CREB transcription factor contributes to long-term modifications in the processing of nociceptive information in the spinal cord (Ma and Quirion, 2001;Miletic et al, 2002;Wu et al, 2002;Song et al, 2005;Crown et al, 2006). The present study shows a similar activation of CREB signaling in the SNL model of neuropathy, and demonstrates the essential and specific contribution of the Ca V 1.2 channel in this process.…”

CCL2 Released from Neuronal Synaptic Vesicles in the Spinal Cord Is a Major Mediator of Local Inflammation and Pain after Peripheral Nerve Injury

“…In addition, CCL2 also evoked the phosphorylation of ERK1/2 in DHSC neurons and microglia. This signaling pathway, activated in DHSC neurons after peripheral noxious stimulation or inflammation (Galan et al, 2002;Ji et al, 2002) and in various cell types during the development of neuropathic pain, was demonstrated previously to participate in pain hypersensitivity developing after peripheral nerve injury (Song et al, 2005;Zhuang et al, 2005). Interestingly, all these effects were blocked by INCB3344, suggesting that CCL2, via CCR2, induced an inflammatory pattern in the DHSC, activated ERK1/2 signaling and, ultimately, evoked pain hypersensitivity.…”