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

Abstract

1 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 (EP_1–3) involved in these sensory disorders by use of 7 synthetic prostanoid analogues. 2 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. 3 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. 4 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. 5 These results demonstrate that PGE₂ may exert allodynia through the EP₁-receptor and hyperalgesia through EP₂- and EP₃-receptors in the mouse spinal cord.