Gap junctions (GJs) are novel molecular targets for pain therapeutics due to their pain-promoting function. INI-0602, a new GJ inhibitor, exerts a neuroprotective role, while its role in neuropathic pain is unclear. The objective was to investigate the analgesic role and mechanisms of INI-0602 in neuropathic pain induced by spared nerve injury (SNI), and whether INI-0602 attenuated pain-induced depression-like behaviors. Rats were randomly assigned to saline treatment groups (sham+NS and SNI+NS) or INI-0602 treatment groups (sham+INI-0602 and SNI+INI-0602). The von Frey test was used to assess pain behavior, and the sucrose preference test, the forced swimming test, and the tail suspension test were used to assess depression-like behaviors. Gap junction intercellular communication (GJIC) was measured by parachute assay. Western blots were used to determine the protein expression. In vitro, INI-0602 significantly suppressed GJIC by decreasing connexin43 and connexin32 expression. In vivo, INI-0602 significantly suppressed mechanical allodynia during initiation (7 days after SNI) and the maintenance phase (21 days after SNI) and simultaneously attenuated accompanying depression-like behaviors. Furthermore, INI-0602 markedly suppressed the activation of astrocytes and microglia on days 7 and 21 by reducing GJIC. Finally, INI-0602 reversed the changes in the brain-derived neurotrophic factor and Nr2b subunits of the N-methyl-D-aspartate receptor in SNI rats, suggesting that these effects of INI-0602 were related to its analgesic effect. Our findings demonstrated that blocking GJs with INI-0602 attenuated mechanical pain hypersensitivity and related depression-like behaviors in SNI rats by reducing glial activation.
aDepartment of Pharmacology, Zhongshan School of Medicine
bDepartment of Anesthesia, The Second Affiliated Hospital, Sun Yat-sen University
cDepartment of Anesthesia, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
* Xiao-Min Zhang, Ling-Zhi Wang and Bo He contributed equally to the writing of this article.
Correspondence to Liang Tao, MD, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China Tel: +86 208 733 2318; e-mail: email@example.com
Correspondence to Qin Wang, MD, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China Tel: +86 208 733 5468; e-mail: firstname.lastname@example.org.
Received December 5, 2018
Accepted January 17, 2019