The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition

Abstract

Peripheral inflammation induces persistent central sensitization characterized by mechanical allodynia and heat hyperalgesia that are mediated by distinct mechanisms. Compared to welldemonstrated mechanisms of heat hyperalgesia, mechanisms underlying the development of mechanical allodynia and contralateral pain are incompletely known. In this study, we investigated the distinct role of spinal JNK in heat hyperalgesia, mechanical allodynia, and contralateral pain in an inflammatory pain model. Intraplantar injection of complete Freund's adjuvant (CFA) induced bilateral mechanical allodynia but unilateral heat hyperalgesia. CFA also induced a bilateral activation (phosphorylation) of JNK in the spinal cord, and the phospho JNK1 (pJNK1) levels were much higher than that of pJNK2. Notably, both pJNK and JNK1 were expressed in GFAP-positive astrocytes. Intrathecal infusion of a selective peptide inhibitor of JNK, D-JNKI-1, starting before inflammation via an osmotic pump, reduced CFA-induced mechanical allodynia in the maintenance phase but had no effect on CFA-induced heat hyperalgesia. A bolus intrathecal injection of D-JNKI-1 or SP600126, a small molecule inhibitor of JNK also reversed mechanical allodynia bilaterally. In contrast, peripheral (intraplantar) administration of D-JNKI-1 reduced the induction of CFA-induced heat hyperalgesia but did not change mechanical allodynia. Finally, CFA-induced bilateral mechanical allodynia was attenuated in mice lacking JNK1 but not JNK2. Taken together, our data suggest that spinal JNK, in particular JNK1 plays an important role in the maintenance of persistent inflammatory pain. Our findings also reveal a unique role of JNK1 and astrocyte network in regulating tactile allodynia and contralateral pain.

MicroRNA-146a-5p attenuates neuropathic pain via suppressing TRAF6 signaling in the spinal cord

“…Also, JNK is an important intracellular kinase in mediating chronic pain, especially mechanical allodynia (Gao et al, 2010;Ma and Quirion, 2002;Zhuang et al, 2006). Spinal inhibition of JNK by its inhibitor SP600125 or D-JNKI-1 not only reversed neuropathic pain (Zhuang et al, 2006), but also decreased SNL-induced CCL2 increase in the spinal cord (Gao et al, 2009).…”

Calpain-2 contributes to neuropathic pain following motor nerve injury via up-regulating interleukin-6 in DRG neurons

“…As of now, the mechanisms underlying mirror pain are still not very clear. Most of previous studies focus on the central nervous system, indicating a key role of activated astrocytes and microglia in spinal dorsal horn in mirror pain (Gao et al, 2010;Hatashita et al, 2008;Obata et al, 2010;Schreiber et al, 2008). In fact, unilateral nerve injury or inflammation also activates satellite glia and macrophages in contralateral DRG of animals with mirror pain (Hatashita et al, 2008;Xie et al, 2006;Zhou et al, 1996).…”

Central Mechanisms of Menthol-Induced Analgesia

“…CFA-induced inflammatory pain was measured as described previously (Gao et al, 2010). Twenty microliters of 50% CFA was injected subcutaneously into the plantar surface of the right hind paw.…”