GPR30 receptor promotes preoperative anxiety-induced postoperative hyperalgesia by up-regulating GABAA-α4ß1δ subunits in periaqueductal gray in female rats.

ABSTRACT

BACKGROUND: G-protein coupled estrogen receptor 30 (GPR30) was proved the specific estrogen receptor relating to mechanical hyperalgesia. Studies have shown that the GABAA receptor subunits α4, ß1, and δ in the periaqueductal gray (PAG) neurons promote the descending facilitation system. This study inquired into whether and how GPR30 and GABAA-α4ß1δ in the PAG promote preoperative anxiety-induced postoperative hyperalgesia in female rats. METHODS: All the female rats were subjected to the single prolonged stress (SPS) to stimulate preoperative anxiety. Subsequently, mechanical allodynia was evaluated before and after the incision, based on the paw withdrawal mechanical threshold (PWMT). The selective GPR30 agonist G1 and antagonist G15 were locally microinjected into the PAG. The expression of GPR30, protein kinase A (PKA), and GABAA receptor subunits α4, ß1, and δ in the PAG neurons were detected using western blotting and immunofluorescence. RESULTS: Behavioral testing revealed that Group S and Group I decreased the nociceptive threshold levels of PWMT in female rats. PWMT in Group S + I decreased more than that of Group S and Group I. Further, results of western blotting showed the expression of GPR30, PKA, and GABAA α4, ß1, and δ subunits significantly up-regulated in Group S + I, and immunofluorescence indicated that the neurons of PAG in Group S + I appeared simultaneously immunopositive for GPR30 and GABAA α4, ß1, and δ receptors. After microinjection of G1 into the PAG, female rats with plantar incision continued to exhibit significant hyperalgesia until postoperative 48 h. On the other hand, microinjection of G15 with SPS and plantar incision procedure relieved postoperative hyperalgesia in female rats. Western blotting demonstrated that intra-PAG injection of G15 markedly decreased the GPR30, PKA, and GABAA α4, ß1, and δ levels in Group G15 + I. CONCLUSIONS: Our results indicate that the GPR30-PKA-GABAAα4ß1δ pathway in the PAG promotes preoperative anxiety-induced postoperative hyperalgesia in female rats. This mechanism might be a potential novel therapeutic target for hyperalgesia in females.