Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 27 (4), 267-276

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

Affiliations

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

Jia-Piao Lin et al. Exp Neurobiol.

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.

Keywords: Chronic constriction injury; Dexmedetomidine; Extracellular signal-regulated kinase; Neuropathic pain; Purinergic receptor; Spinal cord.

Figures

Fig. 1
Fig. 1. CCI induced hyperalgesia and P2X7R upregulation in the spinal dorsal horn. (A) CCI induced mechanical hyperalgesia. The mechanical paw withdrawal threshold on day 7 following CCI surgery was significantly lower than that in the sham group (n=6, mean±SEM, ***p<0.001, ANOVA). (B) CCI induced thermal hyperalgesia. The thermal paw withdrawal latency on day 7 following CCI surgery was significantly lower than that in the sham group (n=6, mean±SEM, p<0.01, ANOVA). (C) Activation of P2X7R/ERK signaling in the spinal dorsal horn after CCI. (D) Upregulation of P2X7R in the spinal dorsal horn after CCI. Western blotting showed that the relative expression of P2X7R was significantly higher in the CCI group than in the sham group (n=4, mean±SEM, *p<0.05, ANOVA). (E) Upregulation of PERK in the spinal dorsal horn after CCI. Western blotting showed that the relative expression of PERK was significantly higher in the CCI group than in the sham group (n=4, mean±SEM, *p<0.05, ANOVA). CCI, chronic constriction injury; Contra, contralateral to CCI; NC, negative control. Scale bar, 100 µm.
Fig. 2
Fig. 2. Dexmedetomidine attenuated the mechanical and thermal hyperalgesia caused by CCI in rats. (A) Dexmedetomidine attenuated mechanical hyperalgesia. The mechanical paw withdrawal threshold in the CCI+DEX group was significantly higher than that in the CCI+NS group from day 8 to day 10 following CCI (n=8, mean±SEM, ***p<0.001, ANOVA). (B) Dexmedetomidine attenuated thermal hyperalgesia. The thermal paw withdrawal latency in the CCI+DEX group was significantly higher than that in the CCI+NS group from day 8 to day 10 following CCI (n=8, mean±SEM, ***p<0.001, ANOVA). CCI, chronic constriction injury; NS, normal saline; DEX, dexmedetomidine.
Fig. 3
Fig. 3. Effect of dexmedetomidine on locomotor function. CCI surgery and intrathecal dexmedetomidine administration at the dosage used in the present study did not affect locomotor function. Naïve, normal rats; Sham, surgery without CCI; CCI, chronic constriction injury; CCI+NS, intrathecally administered 20 µl normal saline following CCI; CCI+DEX, intrathecally administered 2.5 µg/20 µl dexmedetomidine following CCI (Mean±SEM, n=6, five trials).
Fig. 4
Fig. 4. Dexmedetomidine downregulated P2X7R expression and inhibited ERK phosphorylation in the spinal cord in CCI rats. (A) Western blotting showed that the relative level of P2X7R protein was significantly higher in the CCI+NS group than in the sham group (n=5, mean±SEM, **p<0.01, ANOVA). However, compared with P2X7R protein expression in the CCI+NS group, the P2X7R expression level was significantly downregulated in the CCI+DEX group (n=5, mean±SEM, ##p<0.01, ANOVA). (B) Western blotting showed that there was no significant difference in the total ERK protein levels among the sham group, CCI+NS group, or CCI+DEX group (n=4, mean±SEM, p>0.05, ANOVA). (C) Western blotting showed that the relative level of PERK protein was significantly higher in the CCI+NS group than in the sham group (n=5, mean±SEM, *p<0.05, ANOVA). However, compared with the PERK protein expression in the CCI+NS group, the PERK protein expression level was significantly downregulated in the CCI+DEX group (n=5, mean±SEM, #p<0.05, ANOVA). CCI, chronic constriction injury; NS, normal saline; DEX, dexmedetomidine.

Similar articles

See all similar articles

Cited by 5 PubMed Central articles

References

    1. Jensen TS, Baron R, Haanpää M, Kalso E, Loeser JD, Rice AS, Treede RD. A new definition of neuropathic pain. Pain. 2011;152:2204–2205. - PubMed
    1. Torrance N, Ferguson JA, Afolabi E, Bennett MI, Serpell MG, Dunn KM, Smith BH. Neuropathic pain in the community: more under-treated than refractory? Pain. 2013;154:690–699. - PMC - PubMed
    1. Sandkühler J. Models and mechanisms of hyperalgesia and allodynia. Physiol Rev. 2009;89:707–758. - PubMed
    1. Shohayeb B, Diab M, Ahmed M, Ng DC. Factors that influence adult neurogenesis as potential therapy. Transl Neurodegener. 2018;7:4. - PMC - PubMed
    1. Wei H, Jyväsjärvi E, Niissalo S, Hukkanen M, Waris E, Konttinen YT, Pertovaara A. The influence of chemical sympathectomy on pain responsivity and α2-adrenergic antinociception in neuropathic animals. Neuroscience. 2002;114:655–668. - PubMed
Feedback