Spinal NF‐kB activation induces COX‐2 upregulation and contributes to inflammatory pain hypersensitivity

Abstract

Cyclooxygenase-2 (COX-2) is a major contributor to the elevation of spinal prostaglandin E2, which augments the processing of nociceptive stimuli following peripheral inflammation, and dynorphin has been shown to have an important role in acute and chronic pain states. Moreover, the transcription factor, nuclear factor-kappa B (NF-kB), regulates the expressions of both COX-2 and dynorphin. To elucidate the role of spinal NF-kB in the induction of inflammatory pain hypersensitivity, we examined whether activated NF-kB affects pain behavior and the expressions of the mRNAs of COX-2 and prodynorphin following peripheral inflammation. Intrathecal pretreatment with different NF-kB inhibitors, namely, NF-kB decoy or pyrrolidine dithiocarbamate, significantly reduced mechanical allodynia and thermal hyperalgesia following unilateral hindpaw inflammation evoked by complete Freund's adjuvant (CFA). These NF-kB inhibitors also suppressed the activation of spinal NF-kB and the subsequent remarkable elevation of spinal COX-2 mRNA, but not that of prodynorphin mRNA. In addition, the activation of spinal NF-kB following CFA injection was inhibited by intrathecal pretreatments with interleukin-1 beta receptor antagonist or caspase-1 inhibitor. In view of the fact that interleukin-1 beta (IL-1 beta) is the major inducer of spinal COX-2 upregulation following CFA injection, our results suggest that IL-1 beta-induced spinal COX-2 upregulation and pain hypersensitivity following peripheral inflammation are mediated through the activation of the NF-kB-associated pathways.

Nuclear factor-kappa B decoy suppresses nerve injury and improves mechanical allodynia and thermal hyperalgesia in a rat lumbar disc herniation model

“…Previous reports have found that perineural injection of NF-jB decoy just distal to the dorsal root ganglion suppressed cytokine expression in the dorsal root ganglion and also reduced thermal hyperalgesia after spinal nerve ligation. Furthermore, NF-jB decoy injected intrathecally reduced mechanical alloying and thermal hyperalgesia after complete Freund's adjuvant injection into rat hind paws [19,31]. We have also reported that NF-jB decoy could be introduced into DRG neurons effectively in an in vitro and in vivo model, and that NF-jB decoy suppressed mechanical and thermal allodynia in a rat inflammatory foot pain model [11].…”

“…NF-jB decoys have been shown to suppress cytokine expression in DRG, reduce thermal hyperalgesia after spinal nerve ligation, and reduce mechanical hyperalgesia and thermal hyperalgesia in a peripheral inflammatory pain model [19,31]. In a previous report, we showed that an NF-jB decoy was conveyed and transduced into DRG in both an in vivo and in vitro model [11].…”

Spontaneous Glutamatergic Synaptic Activity Regulates Constitutive COX-2 Expression in Neurons OPPOSING ROLES FOR THE TRANSCRIPTION FACTORS CREB (cAMP RESPONSE ELEMENT BINDING) PROTEIN AND Sp1 (STIMULATORY PROTEIN-1)

“…For instance, Kaltschmidt et al (28) show that exposure of neurons to the phorbol 12-myristate 13-acetate (PMA) increases neuronal COX-2 expression in an NF-B -dependent manner. Additionally, NFB is regarded as a strong regulator of inducible COX-2 expression in neurons from diseased brain (29,30) and spinal cord (31,32). Thus, synaptic activity-dependent constitutive COX-2 expression is mechanistically different from injury-induced COX-2 expression.…”

Role of NFκB in an Animal Model of Complex Regional Pain Syndrome–type I (CRPS-I)

“…37 On the contrary, increases in spinal NFkB levels following peripheral IR injury is to our knowledge a new finding, although spinal NFkB activation has been reported following peripheral nerve section 44 and nerve inflammation. 25,33 These peripheral triggers can induce an intraspinal cytokine release, a process that may be mediated by NFkB. 47,51 However, neuropathic painlike symptoms and spinal NFkB activation in CPIP rats are subsequent to IR injury instead of traumatic nerve injury or direct immunological stimulation.…”