ERK MAP Kinase Activation in Superficial Spinal Cord Neurons Induces Prodynorphin and NK-1 Upregulation and Contributes to Persistent Inflammatory Pain Hypersensitivity

Abstract

Activation of ERK (extracellular signal-regulated kinase) MAP (mitogen-activated protein) kinase in dorsal horn neurons of the spinal cord by peripheral noxious stimulation contributes to short-term pain hypersensitivity. We investigated ERK activation by peripheral inflammation and its involvement in regulating gene expression in the spinal cord and in contributing to inflammatory pain hypersensitivity. Injection of complete Freund's adjuvant (CFA) into a hindpaw produced a persistent inflammation and a sustained ERK activation in neurons in the superficial layers (laminae I-IIo) of the dorsal horn. CFA also induced an upregulation of prodynorphin and neurokinin-1 (NK-1) in dorsal horn neurons, which was suppressed by intrathecal delivery of the MEK (MAP kinase kinase) inhibitor U0126. CFA-induced phospho-ERK primarily colocalized with prodynorphin and NK-1 in superficial dorsal horn neurons. Although intrathecal injection of U0126 did not affect basal pain sensitivity, it did attenuate both the establishment and maintenance of persistent inflammatory heat and mechanical hypersensitivity. Activation of the ERK pathway in a subset of nociceptive spinal neurons contributes, therefore, to persistent pain hypersensitivity, possibly via transcriptional regulation of genes, such as prodynorphin and NK-1.

Inhibitory effect of estrogen receptor beta on P2X3 receptors during inflammation in rats

“…Involvement of ERK and c-fos after estrogen replacement in ovariectomized CFA rats ERK is one member of the mitogen-activated protein kinase (MAPK) family, which is known to have different functions in sensory processing [33][34][35]. In the present study, the expressions of ERKand c-fosin the sham, OVX, and estrogen-treated CFArats were investigated.…”

p38 Mitogen-Activated Protein Kinase Is Activated after a Spinal Nerve Ligation in Spinal Cord Microglia and Dorsal Root Ganglion Neurons and Contributes to the Generation of Neuropathic Pain

“…Animals were killed quickly in a CO 2 chamber. The L5 dorsal horns were removed rapidly and homogenized in an SDS sample buffer that contained a mixture of proteinase and phosphatase inhibitors (Ji et al, 2002a). The protein concentration of tissue lysates was determined with a BCA Protein Assay Kit (Pierce, Rockford, IL), and 30 g of protein was loaded in each lane.…”

“…ERK and p38 both have distinct roles in generating pain sensitivity. Activation of ERK in dorsal root ganglion (DRG) and dorsal horn neurons contributes to the development and maintenance of pain hypersensitivity through transcription-dependent and -independent means (Ji et al, 1999(Ji et al, , 2002aAley et al, 2001;Karim et al, 2001;Dai et al, 2002). p38 has been implicated in exaggerated pain states (Watkins et al, 2001b).…”

Altered Expression and Uptake Activity of Spinal Glutamate Transporters after Nerve Injury Contribute to the Pathogenesis of Neuropathic Pain in Rats

“…Activation of Trk receptors in turn initiates downstream cascades, including activation of MAPK (Encinas et al, 1999;Hagemann and Blank, 2001). Activation of MAPK enhances gene expression for a variety of protein elements (Gegelashvili et al, 1997;Hagemann and Blank, 2001;Williams et al, 2001;Ji et al, 2002) and indeed has been shown to induce the expression of both GLT-1 mRNA and protein in astrocytes (Gegelashvili et al, 2000;Zelenaia et al, 2000). Thus the Trk receptor and MAPK pathway may participate in GT upregulation in CCI rats.…”