Effects of intraplantar injections of nociceptin and its N-terminal fragments on nociceptive and desensitized responses induced by capsaicin in mice.
Injection of capsaicin into the hindpaw has been employed as a model of chemogenic nociception in mice. Intraplantar injection of nociceptin (30-240 pmol) produced a significant and dose-dependent antinociceptive activity in the capsaicin test. The nociceptin N-terminal fragments, (1-11) and (1-13), were also active with a potency higher than nociceptin and comparable to nociceptin, respectively. Intraplantar injection of the nociceptin (1-7) fragment had no effect on capsaicin-induced nociception. Antinociception induced by nociceptin or nociceptin (1-13) was reversed significantly by intraplantar co-injection of [Nphe1]nociceptin (1-13)NH2, an orphan opioid receptor-like 1 (ORL1) receptor antagonist, whereas local injection of the antagonist did not interfere with the action of nociceptin (1-11). Nociceptin (1-11) was approximately 2.0-fold more potent than naturally occurring peptide nociceptin, and 10-fold more active than intraplantar morphine. Nociceptive licking/biting response to intraplantar injection of capsaicin was desensitized by repeated injections of capsaicin at the interval of 15 min. Desensitization induced by capsaicin was attenuated significantly by co-injection of nociceptin at much lower doses than antinociceptive ED50 for nociceptin. Capsaicin desensitization was also decreased by co-injection of nociceptin (1-11) and (1-13) to a similar extent. The present results indicate that not only nociceptin but also the N-terminal fragment (1-13) possesses a local peripheral antinociceptive action, which may be mediated by peripheral ORL1 receptors. In addition, the difference of the effective doses suggests that the antinociceptive action and inhibition of capsaicin-induced desenitization by nociceptin, nociceptin (1-11) and (1-13), may involve distinct mechanisms at the level of the peripheral nerve terminal.
Sakurada
Tsukasa
T
Department of Biochemistry, Daiichi College of Pharmaceutical Sciences, Fukuoka 815-8511, Japan. tsukasa@daiichi-cps.ac.jp
Komatsu
Takaaki
T
Moriyama
Tomoko
T
Sasaki
Mika
M
Sanai
Kengo
K
Orito
Tohru
T
Sakurada
Chikai
C
Sakurada
Shinobu
S
D000818:Animals; D002211:Capsaicin / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D009292:Narcotic Antagonists; D018847:Opioid Peptides / Q000008:administration & dosage*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy; D010147:Pain Measurement / Q000379:methods; D010455:Peptides / Q000008:administration & dosage*; D011957:Receptors, Opioid; D014665:Vasodilator Agents / Q000008:administration & dosage*; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D002211:Capsaicin; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010455:Peptides; D011957:Receptors, Opioid; D014665:Vasodilator Agents; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C000722287:Oprl1 protein, mouse