Characterization of EP-receptor subtypes involved in allodynia and hyperalgesia induced by intrathecal administration of prostaglandin E2 to mice.
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 (EP1-3) 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 micrograms 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-omega-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 micrograms kg-1 PGE2: 50 pg-0.5 micrograms kg-1) with two apparent peaks at 0.5 ng kg-1 and 0.5 micrograms kg-1. Sulprostone (EP1 < EP3) and 17-phenyl-omega-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. MB28767 (EP3)showed a monophasic hyperalgesic action over a wide range of dosages at 50 pg-S5 Microg 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.
Minami
T
T
Department of Anesthesiology, Osaka Medical College, Takatsuki, Japan.
Nishihara
I
I
Uda
R
R
Ito
S
S
Hyodo
M
M
Hayaishi
O
O
D000818:Animals; D015232:Dinoprostone / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009619:Nociceptors / Q000187:drug effects; D010146:Pain / Q000139:chemically induced / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects; D011459:Prostaglandins E, Synthetic / Q000008:administration & dosage / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D018078:Receptors, Prostaglandin E / Q000187:drug effects / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects
D011459:Prostaglandins E, Synthetic; D018078:Receptors, Prostaglandin E; D015232:Dinoprostone