Local inhibitory effects of dynorphin A-(1-17) on capsaicin-induced thermal allodynia in rhesus monkeys

Although dynorphin A-(1-17) has been characterized in vitro as a high efficacy κ-opioid receptor agonist, functional studies of dynorphin A-(1-17) following central or systemic administration indicate the involvement of both opioid and non-opioid components. The aim of this study was to investigate whether local administration of dynorphin-related analogs can attenuate capsaicin (8-methyl-N-vanillyl-6-nonenamide)-induced nociception and what type of opioid receptor mediates the local action of dynorphin A-(1-17) in monkeys. Capsaicin (100 μg) was used to evoke a nociceptive response, thermal allodynia, which was manifested as a reduced tail-withdrawal latency in normally innocuous 46°C warm water. Co-administration of dynorphin A-(1- 17) (0.3-10 μg) with capsaicin in the tail dose-dependently inhibited thermal allodynia; however, both non-opioid fragments dynorphin A-(2-17) (10- 300 μg) and dynorphin A-(2-13) (10-300 μg) were ineffective. Local antiallodynia of dynorphin A-(1-17) was antagonized by a small dose (100 μg) of an opioid receptor antagonist, quadazocine, applied s.c. in the tail. Pretreatment with a selective κ-opioid receptor antagonist, nor- binaltorphimine (nor-BNI), s.c. 320 μg in the tail also reversed local antiallodynia of dynorphin A-(1-17). Both locally effective doses of antagonists, when applied s.c. in the back, did not antagonize local dynorphin A-(1-17), indicating that peripheral κ-opioid receptors selectively mediated the local action of dynorphin A-(1-17) in the tail. In addition, a much larger dose of dynorphin A-(1-17) (1000 μg), when administered s.c. in the back or i.m. in the thigh, did not cause sedative or diuretic effects. These results suggest that in vivo opioid actions of dynorphin-related peptides can be differentiated locally in this procedure. They also indicate that local application of peptidic ligands may be a useful medication for localized pain. (C) 2000 Elsevier Science B.V.