(625): Role of peripheral endothelin receptors in an animal model of CRPS-type I

Abstract

Chronic post-ischemic pain (CPIP) is an animal model of CRPS-I developed using an ischemia-reperfusion injury of the rodent hindpaw. CPIP mice exhibit robust mechanical and cold allodynia for at least four weeks. Presently, the contribution of endothelin to nociception has been evaluated in CPIP mice. CPIP is induced by placing a tourniquet (tight fitting O-ring) on one hindlimb of an anesthetized mouse just proximal to the ankle joint for 3 h, with reperfusion prior to termination of anesthesia. We assessed sustained nociceptive behaviors (SNBs) exhibited following intraplantar (i.pl.) injection of 200 pmol of endothelin-1, -2 or -3 (ET-1, ET-2, ET-3) in day 2 CPIP mice. The effects of i.pl. ET-2 were also compared between mice with CPIP (+2 or +7 days), neuropathic (CCI +14 days and SNI +7 days) or inflammatory (CFA +1 day) pain. The effects of an ETA antagonist (BQ-123, 10 nmol, i.pl.) or an ETB antagonist (BQ-788, 30 nmol, i.pl.) or agonist (IRL-1620, 50 pmol, i.pl.) were also assessed on mechanical and cold allodynia and ET-2-induced SNBs in CPIP mice. Compared to sham, CPIP mice exhibited prolonged SNBs after injection of ET-2, but not ET-1 or ET-3. However, ET-2 did not produce significant SNBs in mice with neuropathic or inflammatory pain. The ETB agonist, but not ETA or ETB antagonists, reduced both ET-2-induced SNBs and mechanical allodynia in CPIP mice. In conclusion, CPIP mice appear to have increased nociceptive responses to ET-2, yet also are relieved of both mechanical allodynia and ET-2-induced nociception by treatment with an ETB agonist. CPIP mice may have an upregulation of ETB receptors, which produce antinociceptive effects, yet also exhibit an unexplained nociceptive response to ET-2. Further study of the differential involvement of the potential ETB subtypes in these two distinct observations is needed.