Dexmedetomidine Attenuates Neuropathic Pain by Inhibiting P2X7R Expression and ERK Phosphorylation in Rats

Abstract

α2-Adrenoceptor agonists attenuate hypersensitivity under neuropathic conditions. However, the mechanisms underlying this attenuation remain largely unknown. In the present study, we explored the potential roles of purinergic receptor 7 (P2X7R)/extracellular signal-regulated kinase (ERK) signaling in the anti-nociceptive effect of dexmedetomidine in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. An animal model of CCI was adopted to mimic the clinical neuropathic pain state. Behavioral hypersensitivity to mechanical and thermal stimuli was determined by von Frey filament and Hargreaves' tests, and the spinal P2X7R expression level and ERK phosphorylation were analyzed using western blot analysis and immunohistochemistry. In parallel with the development of mechanical and thermal hyperalgesia, a significant increase in P2X7R expression was noted in the ipsilateral spinal cord on day 7 after CCI. Intrathecal administration of dexmedetomidine (2.5 µg) for 3 days not only attenuated neuropathic pain but also inhibited the CCI-induced P2X7R upregulation and ERK phosphorylation. Intrathecal dexmedetomidine administration did not produce obvious effects on locomotor function. The present study demonstrated that dexmedetomidine attenuates the neuropathic pain induced by CCI of the sciatic nerve in rats by inhibiting spinal P2X7R expression and ERK phosphorylation, indicating the potential therapeutic implications of dexmedetomidine administration for the treatment of neuropathic pain.

C-X-C Motif Chemokine 10 Contributes to the Development of Neuropathic Pain by Increasing the Permeability of the Blood–Spinal Cord Barrier

“…In this study, we investigated the putative link between CXCL10/CXCR3 signaling-mediated BSCB disruption and neuropathic pain. As in our previous studies, CCI group rats exhibited robust post-operative behavioral hypersensitivity to mechanical stimuli, and this hypersensitivity persisted throughout the experimental period (29,32). We also determined that CCI induced CXCL10/CXCR3 signaling, increased BSCB permeability, and promoted T cell migration into the spinal dorsal horn.…”

“…Hyperalgesia was assessed based on paw withdrawal responses to a calibrated series of von Frey filaments (Stoelting; Wood Dale, IL, USA) as described in one of our earlier publications (32). In brief, the rats were individually placed in a chamber (20 cm × 10 cm × 20 cm) in which the floor was a customized platform consisting of a grid of iron wires with 10-mm spacings between wires.…”

N-Acetylcysteine causes analgesia in a mouse model of painful diabetic neuropathy

“…Analgesic drugs, such as dexmetomidine, type-2 cannabinoid receptor agonists, and ketamine alleviate neuropathic pain by restraining MAPK activation in the spinal cord. [70][71][72] In dorsal horn neurons, MAPK phosphorylates and inhibits K v 4.2 channels, which mediate type-A potassium currents and are involved in pain plasticity. [73][74][75] It is possible that NAC treatment in diabetic mice enhances the activity of K v 4.2 channels, therefore reducing excitability of secondary order neurons in the dorsal horns of the spinal cord.…”

Dexmedetomidine versus ketamine in attenuating neuropathic pain through modulating STING/TBK pathway to modulate spinal ER-phagy in neuropathic pain model

“…Dexmedetomidine, a selective α2 adrenergic receptor (AR) agonist, provided analgesic potency via systemic administration, also, low does of dexmedetomidine relieved tactile allodynia induced by neuropathic pain model (5). Moreover, study demonstrated that dexmedetomidine might a better adjuvant for clinical procedure and pain management for neuropathic pain in clinic (6,7).…”