Antinociceptive effects of two deltorphins analogs in the tail-immersion test in rats

• Published in: Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2013-01, Vol.39, p.103-110
• Main Authors: Kotlinska, J.H., Gibula-Bruzda, E., Witkowska, E., Chung, N.N., Schiller, P.W., Izdebski, J.
• Format: Article
• Language: English
• Subjects: agonists; analgesic effect; Analgesics, Opioid - administration & dosage; Analgesics, Opioid - pharmacology; Animals; antagonists; Deltorphins analogs; Drug Synergism; Drug Tolerance; Male; Morphine; Morphine - administration & dosage; Morphine - pharmacology; Naltrexone - analogs & derivatives; Naltrexone - pharmacology; Narcotic Antagonists - pharmacology; Nociception; Nociception - drug effects; Oligopeptides - administration & dosage; Oligopeptides - pharmacology; pain; Pain Measurement; Rats; Rats, Wistar; receptors; Receptors, Opioid, delta - agonists; Receptors, Opioid, delta - antagonists & inhibitors; Receptors, Opioid, delta - metabolism; Receptors, Opioid, kappa - agonists; Receptors, Opioid, kappa - antagonists & inhibitors; Receptors, Opioid, kappa - metabolism; Tail-immersion test; Tolerance
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2012.11.008

► Deltorphins analogs (DEL-6 and DK-4) induced antinociception in thermal pain. ► These effects were attenuated by MOR and DOR antagonists. ► Non-effective doses of DEL-6 and morphine produced additive antinociceptive action. ► Both deltorphins analogs produced low cross-tolerance with morphine. ► Deltorphins analogs involve MOR and DOR to exert their antinociceptive effects. The antinociceptive effects of analogs of deltorphins: cyclo(Nδ,Nδ-carbonyl-d-Orn2, Orn4)deltorphin (DEL-6) and deltorphin II N-(ureidoethyl)amide (DK-4) after intracerebroventricular (i.c.v.) administration were investigated in the tail-immersion test in rats. Morphine, the most commonly used μ-opioid receptors (MOR) agonist, was employed as a reference compound. The contribution of the MOR, δ-(DOR) and κ-opioid receptors (KOR) in antinociceptive effects of the deltorphins analogs was studies using selective antagonists of these receptors. The results indicated that DK-4 (5, 10 and 20nmol) and DEL-6 (5, 10 and 20nmol) were the most effective in alleviating thermal pain at the dose of 20nmol. The antinociceptive potency of DEL-6 at the dose of 20nmol was approximately equal but DK-4 at the dose of 20nmol was less effective than morphine at the dose of 13nmol. DOR antagonist – naltrindole (NTI, 5nmol) very strongly and, to the lower extent MOR antagonist – β-funaltrexamine (β-FNA, 5nmol), inhibited antinociceptive effect of DK-4 (20nmol). In turn, β-FNA was more potent than NTI in inhibition of the antinociceptive effects of DEL-6. Co-administration of DEL-6 and morphine at doses of 5nmol, which do not produce measurable antinociception, generated additive antinociceptive effect. Chronic intraperitoneal (i.p.) injection of morphine (9 days) displayed a marked analgesic tolerance to the challenge dose of morphine and a slight cross-tolerance to challenge doses of DEL-6 and DK-4, given i.c.v. These findings indicate that the new deltorphin analogs recruit DOR and MOR to attenuate the nociceptive response to acute thermal stimuli.