Activation of the Neuronal Extracellular Signal-Regulated Kinase 2 in the Spinal Cord Dorsal Horn Is Required for Complete Freund's Adjuvant-Induced Pain Hypersensitivity

Abstract

Extracellular signal-regulated kinase 1 (ERK1) and ERK2 signaling in the spinal cord dorsal horn (SCDH) has been implicated in injuryinduced pain hypersensitivity. Available ERK pathway inhibitors cannot distinguish between ERK1 and ERK2, nor can they differentially target the expression of neuronal or glial ERK1/2. We selectively inhibited the expression of ERK2 in neurons of the adult mouse SCDH by use of an ERK2 small interfering RNA (siRNA) delivered by a neurotropic adenoassociated viral vector. In situ hybridization revealed a siRNA vector-induced decrease in ERK2 mRNA in the ipsilateral SCDH. Immunohistochemistry showed a decreased neuronal phospho-ERK1/2 (pERK1/2), and Western blot analysis revealed that both ERK2 expression and phosphorylation were reduced by the siRNA vector. In contrast, basal ERK1 expression was not affected, although pERK1 was slightly increased. The siRNA vector-induced knockdown of ERK2 expression in the SCDH did not alter the baseline mechanical or thermal paw withdrawal thresholds. Hindpaw intraplantar injection of complete Freund's adjuvant (CFA) produced peripheral inflammation, mechanical allodynia, and thermal hyperalgesia in vector control animals that persisted for at least 96 h. It also caused an increase in SCDH ERK1 and ERK2 levels at 96 h and pERK1 and pERK2 levels at 1 and 96 h. The ERK2 siRNA vector prevented changes in ERK1, ERK2, and pERK2. In addition, the siRNA vector protected the animals from developing mechanical allodynia and thermal hyperalgesia throughout the 96 h after CFA. These findings indicate that ERK2 in the SCDH neurons is critical for the development of inflammatory pain hypersensitivity.

Peripheral noxious stimulation reduces withdrawal threshold to mechanical stimuli after spinal cord injury: Role of tumor necrosis factor alpha and apoptosis

“…ERK [21,91,96] and JNK/c-Jun [34,96] pathways are implicated in spinal pain processing. The decrease in ERK expression at earlier time points, an effect that could result from neuronal death [91], suggests ERK had a limited role in the present paradigm.…”

Synergistic antinociceptive effects of N-methyl-D-aspartate receptor antagonist and electroacupuncture in the complete Freund's adjuvant-induced pain model

“…The goal of the present study was to observe alterations in the spinal NMDA NR2B subunit, ERK, p38 and CREB activation in CFA-injected rats due to EA and NMDAR antagonist treatment. The intraplantar administration of CFA has been shown to induce mechanical allodynia and thermal hyperalgesia on the ipsilateral hindpaw and L4-5 nerve roots or inflammation of the dorsal root ganglion (17,18). Therefore, we examined the inhibitory effects of EA stimulation and dizocilpine injection on heat paw withdrawal latency.…”

Fufang Kushen injection inhibits sarcoma growth and tumor-induced hyperalgesia via TRPV1 signaling pathways

“…Deletion of this receptor results in inhibiting experimental inflammatory hyperalgesia and neurogenic inflammation pain [13]. The ERK signal pathway has recently been identified as central to pain sensitivity in inflammatory and neuropathic pain models [14–16]. A noxious stimulus or tissue injury rapidly leads to phosphorylation of ERK within a few minutes, which correlates well with the rate of development of pain hypersensitivity [17].…”