Title: Characterization of EP‐receptor subtypes involved in allodynia and hyperalgesia induced by intrathecal administration of prostaglandin E<sub>2</sub> to mice
Abstract: Intrathecal (i.t.) administration of prostaglandin E 2 (PGE 2 ) 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 (EP 1–3 ) involved in these sensory disorders by use of 7 synthetic prostanoid analogues. Sulprostone (EP 1 < EP 3 ) 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 PGE 2 . 17‐Phenyl‐ω‐trinor PGE 2 (EP 1 > EP 3 ) and 16,16‐dimethyl PGE 2 (EP 1 = EP 2 = EP 3 ) were as potent as PGE 2 in inducing allodynia, and more potent than sulprostone. Butaprost (EP 2 ), 11‐deoxy PGE 1 (EP 2 = EP 3 ), MB 28767 (EP 3 ), and cicaprost (prostaglandin I 2 (IP‐) receptor) induced allodynia, but with much lower scores. 13,14‐Dihydro‐15‐keto PGE 2 , a metabolite of PGE 2 , did not induce allodynia. 16,16‐Dimethyl PGE 2 as well as PGE 2 induced hyperalgesia over a wide range of dosages (16,16‐dimethyl PGE 2 : 5 pg–0.5 μg kg −1 PGE 2 : 50 pg–0.5 μg kg −1 ) with two apparent peaks at 0.5 ng kg −1 and 0.5 μg kg −1 . Sulprostone (EP 1 < EP 3 ) and 17‐phenyl‐ω‐trinor PGE 2 (EP 1 > EP 3 ) 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 (EP 3 ) showed a monophasic hyperalgesic action over a wide range of dosages at 50 pg–5 μg kg −1 . Butaprost (EP 2 ) induced hyperalgesia at doses higher than 50 ng kg −1 . These results demonstrate that PGE 2 may exert allodynia through the EP 1 ‐receptor and hyperalgesia through EP 2 ‐ and EP 3 ‐receptors in the mouse spinal cord.