Characterization of EP‐receptor subtypes involved in allodynia and hyperalgesia induced by intrathecal administration of prostaglandin E2 to mice

Abstract

Intrathecal (i.t.) administration of prostaglandin E2 (PGE2) to conscious mice induced allodynia, a state of discomfort and pain evoked by innocuous tactile stimuli, and hyperalgesia as assessed by the hot plate test. We characterized prostaglandin E receptor subtypes (EP1–3) involved in these sensory disorders by use of 7 synthetic prostanoid analogues. Sulprostone (EP1 < EP3) induced allodynia over a wide range of dosages from 50 pg to 5 μg kg−1. The maximal allodynic effect was observed at 5 min after i.t. injection, and the response gradually decreased over the experimental period of 50 min. This sulprostone‐induced allodynia showed a time course similar to that induced by PGE2. 17‐Phenyl‐ω‐trinor PGE2 (EP1 > EP3) and 16,16‐dimethyl PGE2 (EP1 = EP2 = EP3) were as potent as PGE2 in inducing allodynia, and more potent than sulprostone. Butaprost (EP2), 11‐deoxy PGE1 (EP2 = EP3), MB 28767 (EP3), and cicaprost (prostaglandin I2 (IP‐) receptor) induced allodynia, but with much lower scores. 13,14‐Dihydro‐15‐keto PGE2, a metabolite of PGE2, did not induce allodynia. 16,16‐Dimethyl PGE2 as well as PGE2 induced hyperalgesia over a wide range of dosages (16,16‐dimethyl PGE2: 5 pg–0.5 μg kg−1 PGE2: 50 pg–0.5 μg kg−1) with two apparent peaks at 0.5 ng kg−1 and 0.5 μg kg−1. Sulprostone (EP1 < EP3) and 17‐phenyl‐ω‐trinor PGE2 (EP1 > EP3) showed a bell‐shaped hyperalgesia at lower doses of 5 pg–5 ng kg−1 and 50 pg–50 ng kg−1, respectively. MB 28767 (EP3) showed a monophasic hyperalgesic action over a wide range of dosages at 50 pg–5 μg kg−1. Butaprost (EP2) induced hyperalgesia at doses higher than 50 ng kg−1. These results demonstrate that PGE2 may exert allodynia through the EP1‐receptor and hyperalgesia through EP2‐ and EP3‐receptors in the mouse spinal cord. 1994 British Pharmacological Society