morphinans and deltorphin

The identification of opioid delta receptor subtypes in mouse brain led to the investigation of the nature of the opioid delta receptors in the mouse isolated vas deferens in vitro. Noncumulative concentration-effect curves were constructed for DPDPE (delta 1 agonist) and [D-Ala2, Glu4]deltorphin (delta 2 agonist) in control tissues, or in tissues which had been incubated with either [D-Ala2, Leu5, Cys6] enkephalin (DALCE) (noncompetitive delta 1 antagonist) or 5'-naltrindole isothiocyanate (5'-NTII) (noncompetitive delta 2 antagonist). Incubation of the tissues with DALCE, under either oxygenated or nonoxygenated conditions, did not alter the concentration-effect curves for either agonist. In contrast, incubation of the tissues with 5'-NTII resulted in a significant rightward displacement of the concentration-effect curves of both DPDPE and [D-Ala2, Glu4] deltorphin. Additionally, naltriben, a selective and competitive delta 2 antagonist, showed no significant difference in its ability to antagonize a fixed, submaximal concentration of either DPDPE or [D-Ala2, Glu4]deltorphin. Furthermore, there was no significant difference in the affinity of naloxone (i.e., pA2) at the receptor(s) acted upon by either DPDPE or [D-Ala2, Glu4]deltorphin. Tolerance to DPDPE or [D-Ala2, Glu4]deltorphin was produced by incubation of the tissues with these agonists; construction of the [D-Ala2, Glu4]deltorphin concentration-effect curve in DPDPE-tolerant tissues demonstrated cross-tolerance between these agonists and, conversely, construction of DPDPE concentration-effect curves in [D-Ala2, Glu4]deltorphin-tolerant tissues revealed cross-tolerance between these agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzylidene Compounds; Drug Tolerance; Enkephalin, D-Penicillamine (2,5)-; Enkephalin, Leucine-2-Alanine; Enkephalins; In Vitro Techniques; Isothiocyanates; Male; Mice; Mice, Inbred ICR; Morphinans; Naltrexone; Oligopeptides; Receptors, Opioid, delta; Thiocyanates; Vas Deferens

When given i.c.v. in rats deltorphins induced a syndrome of behavioural stimulation consisting of increased locomotion rearing and sniffing. The increased locomotor activity and rearing were dose-related over the range of 0.13 to 3.8 nmol/rat for [D-Ala2]deltorphin II (DADELT II) and 1.04 to 20.8 nmol/rat for deltorphin. The delta-selective antagonist, naltrindole (10 mg/kg i.p.), completely abolished the behavioural stimulation induced by 1.3 nmol/rat of DADELT II and shifted the dose-response curve to the right, without decreasing the maximum effect. The mu-preferring antagonist, naloxone, was able to antagonize the DADELT II-induced locomotor activity but only at very high doses (10 and 20 mg/kg i.p.). The i.v. administration of a large dose (10 mg/kg) of the mu 1-selective antagonist, naloxonazine, did not affect the DADELT II response. At doses up to 38 nmol/rat, the i.c.v. injection of DADELT II never induced analgesia. At doses over 20.8 nmol/rat, deltorphin always induced spontaneous controlateral barrel rotations and circling, responses which were not blocked by prior administration of naloxone or haloperidol. In studies performed on the social behaviour of rats, i.c.v. administration of 0.38 nmol/rat of DADELT II was ineffective, while 1.3 nmol/rat increased the number of social contacts. Regression analysis showed that the increase in social contacts was a primary effect of the peptide, not correlated with the increased locomotor activity.

Topics: Analgesics; Animals; Behavior, Animal; Indoles; Injections, Intraventricular; Male; Morphinans; Motor Activity; Naloxone; Naltrexone; Oligopeptides; Pain Measurement; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Social Behavior; Stereotyped Behavior

Although numerous data support the existence of a presynaptic inhibitory control by opioids of substance P-containing primary afferent fibres entering the dorsal horn of the spinal cord, the exact nature of the opioid receptor involved in this control is still a matter of debate. In the present study, the potential role of delta opioid receptors was investigated by looking for the possible effects of selective delta ligands on the in vivo release of substance P-like material from the whole spinal cord in halothane-anaesthetized rats. Perfusion of the intrathecal space allowed the collection of substance P-like material that was released at a constant rate of approximately 0.65 pg substance P equivalents/min for at least 135 min. The addition of Tyr-D-Thr-Gly-Phe-Leu-Thr (10 microM) or dermenkephalin (10 microM), two selective delta agonists, to the perfusing fluid produced a marked reduction (-50-65%) in substance P-like material outflow which could be prevented by the selective delta antagonist naltrindole (10 microM) but not by naloxone (10 microM), which acts preferentially on mu opioid receptors. Furthermore, naltrindole alone (or the association of this antagonist plus dermenkephalin) enhanced the outflow of substance P-like material (+ 170%) as expected from the blockade of a tonic inhibitory control due to the stimulation of delta receptors by endogenous opioids.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Sequence; Animals; Depression, Chemical; Indoles; Injections, Spinal; Male; Molecular Sequence Data; Morphinans; Naloxone; Naltrexone; Oligopeptides; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Secretory Rate; Spinal Cord; Substance P