Analgesic Efficacy of α(2) Adrenergic Receptor Agonists Depends on the Chronic State of Neuropathic Pain: Role of Regulator of G Protein Signaling 4.

Affiliation

Yoon SY(1), Roh DH(2), Yeo JH(2), Woo J(3), Han SH(4), Kim KS(5).
Author information:
(1)Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; College of Korean Medicine, Dongshin University, Gunjae Road 185, Naju-si, Jeonnam 58245, Republic of Korea. Electronic address: [Email]
(2)Department of Oral Physiology, School of Dentistry, Kyung Hee University, Seoul 02454, Republic of Korea.
(3)Research Animal Resource Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
(4)Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
(5)Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Research Animal Resource Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea. Electronic address: [Email]

Abstract

The analgesic effect of alpha-2 adrenergic receptor (α2AR) agonists, which relieve chronic neuropathic pain, is highly variable among individuals. Here, we used a mouse model of spared nerve injury (SNI) to show that treatment time after the establishment of neuropathic pain was important for the variability in the analgesic efficacy of α2AR agonists, which was related to the activity of regulator of G-protein signaling protein 4 (RGS4). Intrathecal treatment with α2AR agonists, clonidine (0.1-1 nmol) or dexmedetomidine (0.3-1 nmol), relieved mechanical allodynia and thermal hyperalgesia on postoperative day (POD) 14, but their efficacy was weaker on POD28 and absent on POD56. The RGS4 level of plasma membrane was increased on POD56 compared to that on POD14. Moreover, in RGS4-deficient or RGS4 inhibitor (CCG50014)-treated mice, the analgesic effect of the α2AR agonists was conserved even on POD56. The increased plasma membrane RGS4 expression and the reduced level of active Gαi after clonidine injection on POD56 were completely restored by CCG50014. Higher doses of clonidine (10 nmol) and dexmedetomidine (3 nmol) relieved neuropathic pain on POD56 but were accompanied with serious side effects. Whereas, the coadministration of CCG50014 with clonidine (1 nmol) or dexmedetomidine (1 nmol) did not cause side effects. These findings demonstrated that SNI-induced increase in plasma membrane RGS4 expression was associated with low efficacy of α2AR agonists in a model of persistent, chronic neuropathic pain. Furthermore, α2AR agonist administration together with RGS4-targeted intervention represents a novel strategy for the treatment of neuropathic pain to overcome dose-limiting side effects.