Pharmacological characterization of the nociceptin receptor mediating hyperalgesia in the mouse tail withdrawal assay.
1. The newly discovered neuropeptide nociceptin (NC) has recently been reported to be the endogenous ligand of the opioid-like orphan receptor. Despite its structural similarity to opioids, when injected intracerebroventricularly (i.c.v.) in the mouse, NC exerts a direct hyperalgesic effect and reverses opioid-induced analgesia. In the present investigation, these two effects of NC were evaluated under the same experimental conditions; in addition, a pharmacological characterization of the receptor mediating these central effects of NC was attempted. 2. NC caused a dose dependent (0.1-10 nmol/mouse), naloxone-insensitive reduction of tail withdrawal latency with a maximal effect of about 50% of the reaction time observed in saline injected mice. In the same range of doses, NC inhibited morphine (1 nmol/mouse) induced analgesia. 3. The effects of the natural peptide were mimicked by NCNH2 and NC(1-13)NH2 (all tested at 1 nmol/mouse) while 1 nmol NC(1-9)NH2 was found to be inactive either in reducing tail withdrawal latency or in preventing morphine analgesia. 4. [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 ([F/G]NC(1-13)NH2), which has been shown to antagonize NC effects in the mouse vas deferens, acted as an agonist, mimicking NC effects in both the experimental paradigms. In addition, when NC and [F/G]NC(1-13)NH2 were given together, their effects were additive. 5. These results demonstrate that both the direct hyperalgesic action and the anti-morphine effect of NC can be studied under the same experimental conditions in the mouse tail withdrawal assay. Moreover, the pharmacological characterization of the NC functional site responsible for these actions compared with the peripherally active site, indicates the existence of important differences between peripheral and central NC receptors.
Calò
G
G
Department of Experimental and Clinical Medicine, University of Ferrara, Italy.
Rizzi
A
A
Marzola
G
G
Guerrini
R
R
Salvadori
S
S
Beani
L
L
Regoli
D
D
Bianchi
C
C
D000698:Analgesia; D000701:Analgesics, Opioid; D000818:Animals; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D051379:Mice; D009020:Morphine; D009292:Narcotic Antagonists; D018847:Opioid Peptides / Q000378:metabolism* / Q000494:pharmacology; D010147:Pain Measurement; D011957:Receptors, Opioid / Q000378:metabolism*; D013623:Tail / Q000502:physiology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D000701:Analgesics, Opioid; D009020:Morphine; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C000722287:Oprl1 protein, mouse