beta-funaltrexamine and bremazocine

The kappa-opioid agonists U50488H, bremazocine, and BRL52537, and the mu-opioid agonist morphine were compared in their ability to modify spontaneous motor activity in male NMRI mice. Higher, analgesic doses of the kappa-agonists reduced rearing, motility, and locomotion in nonhabituated mice. These effects, as well as the analgesic action of U50488H, were blocked by the selective kappa-opioid antagonists nor-binaltorphimine and DIPPA. In contrast, lower, subanalgesic doses (1.25 and 2.5 mg/kg for U50488H; 0.15 and 0.075 mg/kg for bremazocine, and 0.1 mg/kg for BRL52537) time dependently increased motor activity. The stimulatory effects of U50488H and bremazocine were not observed in habituated animals and were reduced by dopamine depletion. Surprisingly, the stimulatory effects of U50488H and bremazocine were not blocked by nor-binaltorphimine and DIPPA but they were completely eliminated by naloxone (0.1 mg/kg). The effects of morphine were dose-dependent; an initial limited suppression was followed by increased motility and locomotion (but not rearing) with a peak effect at 20 mg/kg both in habituated and nonhabituated mice. The selective mu-opioid antagonist beta-funaltrexamine blocked morphine-induced motor stimulation and analgesia but failed to affect the analgesic and motor stimulatory effects of U50488H. The results indicate that kappa-opioid agonists interact with different functional subtypes of opioid receptors. A stimulatory, naloxone-sensitive but nor-binaltorphimine- and DIPPA-insensitive subtype of opioid receptor appears to operate only when the dopamine system is tonically active in nonhabituated animals. At higher doses, kappa-agonists produce analgesia and motor suppression, effects mediated by a "classic" (inhibitory) kappa-opioid receptor.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acetamides; Animals; Benzomorphans; Dose-Response Relationship, Drug; Isothiocyanates; Male; Mice; Morphine; Motor Activity; Naloxone; Naltrexone; Receptors, Opioid, kappa; Time Factors

The effect of pretreatment with the kappa receptor nonequilibrium antagonist, (-)-UPHIT (1S,2S-trans-2-isothiocyanato-4,5-dichloro-N-methyl-N-[2-(1-pyrrol idinyl) cyclohexyl]benzeneacetamide), on U69,593 [(5 alpha,7 alpha,8 beta)-(-)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5) dec-8-yl)benzeneacetamide]- and bremazocine-induced antinociception was examined in mice. Both U69,593 and bremazocine produced antinociception in the warm water tail-flick test after i.c.v. administration. Pretreatment with the kappa antagonist, nor-binaltorphimine, at doses shown not to affect [D-Ala2, NMePhe4, Gly-ol]enkephalin- (mu-agonist) or [D-Pen2, D-Pen5]enkephalin (delta-agonist)-induced antinociception, significantly attenuated the effects of U69,593 and bremazocine, suggesting actions of these agonists at kappa receptors. Furthermore, beta-funaltrxamine (mu antagonist) and ICI 174,864 [N,N,-diallyl-Tyr-(alpha-aminoisobutyric acid)2-Phe-Leu-OH] (delta antagonist), had no effect on U69,593 or bremazocine in this test providing further evidence of kappa receptor-mediated activity. Pretreatment with (-)-UPHIT produced no effect alone and a long-lasting (up to 48 hr) antagonism of U69,593, but not bremazocine, antinociception. The antagonist actions of (-)-UPHIT did not alter the antinociceptive effects of [D-Ala2, NMePhe4, Gly-ol]enkephalin or [D-Pen2, D-Pen5]enkephalin. These data suggest that (-)-UPHIT is a selective, long-lasting kappa antagonist which can differentially antagonize the antinociception produced by these two kappa agonists. These data provide evidence in vivo supportive of kappa receptor subtypes in the mouse, and suggest that (-)-UPHIT may be a useful probe for the exploration of kappa receptor heterogeneity.

Topics: Analgesics; Animals; Benzeneacetamides; Benzomorphans; Cyclohexanes; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred ICR; Naltrexone; Narcotic Antagonists; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

A variety of data support the hypothesis of an opiate receptor complex composed of distinct, yet interacting mu and delta binding sites (termed mu cx and delta cx to indicate binding sites 'in the complex'), in addition to independent mu and delta binding sites, termed mu ncx and delta ncx, to indicate binding sites 'not in the complex'. Ligand binding studies using membranes and slide-mounted sections of rat brain support the hypothesis that the irreversible mu-antagonist beta-funaltrexamine (FNA) selectively alkylates the opiate receptor complex, altering the binding of mu agonists to the mu cx binding site and the binding of [3H][D-Ala2,D-Leu5]enkephalin to the delta cx site. Previous studies demonstrated that the chronic administration of morphine to rats selectively 'upregulates' the opiate receptor complex. In contrast, the chronic administration of naltrexone upregulates several types of opioid receptors, including kappa, the delta ncx binding site, and multiple binding sites labeled by mu agonists. A prediction based upon these observations is that, using [3H][D-Ala2,MePhe4,Gly-ol5]enkephalin to label mu binding sites, chronic morphine should upregulate only the mu cx binding site, whereas chronic naltrexone should additionally up-regulate the mu ncx binding site. In this study we test and confirm this hypothesis, using sensitivity to FNA to define the mu cx binding site. The implications of these data for models of the opioid receptors and the mechanism(s) of tolerance and dependence are discussed.

Topics: Animals; Benzomorphans; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; In Vitro Techniques; Male; Morphine; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

We studied the effect of opiates acting preferentially on mu receptors, like morphine, methadone and fentanyl (mu agonists) and on kappa receptors, like U50,488, bremazocine and tifluadom (kappa agonists) on the release of dopamine (DA) and of its metabolites, dihydroxyphenylacetic acid and homovanillic acid, from the nucleus accumbens and from the dorsal caudate of freely moving rats using brain dialysis coupled to high-performance liquid chromatography with electrochemical detection. Spontaneous behavior was videotaped and analyzed by estimating the percentage of time spent by the animals in performing certain specific behavioral items. Mu agonists stimulated DA-release and metabolism in the accumbens at lower doses than in the caudate. Maximal stimulation of DA release did not exceed 100% except after high doses of methadone (10 mg/kg) which stimulated DA release in the accumbens by more than 300%, possibly as a result of hypoxia. Stimulation of DA release was associated to stimulation of behavior at low doses and to a biphasic inhibitory-stimulatory syndrome after higher doses of the opiates. Pretreatment with low doses of naloxone (0.1 mg/kg s.c.) or with the irreversible mu antagonist beta-funaltrexamine (10 nmol i.c.v.) increased the ED50 for the stimulation of DA release by the three opiates. In contrast with mu agonists, agonists of kappa receptors like U50,488, bremazocine and tifluadom decreased DA release in the accumbens and in the caudate and reduced motor activity. These effects were antagonized only by rather high doses of naloxone (2.5 mg/kg s.c.) and were not affected by pretreatment with beta-funaltrexamine (10 nmol i.c.v.).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzomorphans; Caudate Nucleus; Dopamine; Male; Methadone; Morphine; Motor Activity; Naloxone; Naltrexone; Nucleus Accumbens; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Reward; Septal Nuclei

Buprenorphine was studied for its effects on urinary output to determine if it was an agonist, partial agonist, or antagonist at the kappa receptor. Buprenorphine was a potent antagonist of bremazocine-induced urination and had no kappa agonist activity. Thus, the high affinity that buprenorphine has for the kappa receptor results in potent kappa receptor antagonist activity in vivo.

Topics: Animals; Benzomorphans; Buprenorphine; Diuresis; Drug Combinations; Male; Naltrexone; Rats; Rats, Inbred Strains; Receptors, Opioid

In rhesus monkeys, kappa opioid agonists have been shown to increase urinary output, increase tail-withdrawal latencies from warm water and produce distinct discriminative stimulus effects. In order to explore further the relation between these effects and activity at the kappa opioid receptor type, the antagonist activity of quadazocine against several kappa opioid agonists was examined with the tail-withdrawal and drug-discrimination procedures. Quadazocine dose dependently antagonized the increases in tail-withdrawal latency produced by the kappa agonists bremazocine, ethylketazocine and U-50, 488, as well as the discriminative stimulus effects of these drugs. The dose-ratio analysis of Schild revealed apparent pA2 values for quadazocine in combination with bremazocine, ethylketazocine and U-50, 488 of 6.1, 6.4 and 6.4, respectively, with the tail-withdrawal procedure and 6.3, 6.4 and 6.1, respectively, with the drug-discrimination procedure. Quadazocine also antagonized the effects of a mu agonist (morphine) in the tail-withdrawal procedure, and the apparent pA2 value for these data was 8.2. The activity of the mu-selective alkylating agent, beta-funaltrexamine (beta-FNA), was examined alone and in combination with the kappa agonist ethylketazocine in the urinary-output, tail-withdrawal and drug-discrimination procedures. At about 30 to 60 min postinjection, beta-FNA alone produced ethylketazocine-appropriate responding under the drug-discrimination procedure and increased urine output but did not increase tail-withdrawal latencies. At 24 to 48 hr postinjection, beta-FNA did not antagonize effects of ethylketazocine in any of the three procedures.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Azocines; Benzomorphans; Cyclazocine; Diuresis; Endorphins; Ethylketocyclazocine; Female; Hot Temperature; Macaca mulatta; Male; Morphine; Naltrexone; Narcotic Antagonists; Pyrrolidines; Reaction Time; Tail

The agonist and antagonist activity of bremazocine at opioid receptors in the guinea-pig myenteric plexus preparation was determined in untreated tissues and in tissues in which either mu-9 or kappa-opioid receptors were blocked preferentially. After pretreatment of the tissue with beta-funaltrexamine for 90 min followed by washing out, the IC50 value of the selective mu-ligand [D-Ala2,MePhe4,Gly-ol5]enkephalin was increased 67 fold whereas the IC50 values of the selective kappa-ligand U-69,593 and of the non-selective kappa-ligand bremazocine were not significantly changed. In this experimental design bremazocine acted only on kappa-receptors. After pretreatment of the tissue with beta-chlornaltrexamine and 10 microM of the mu-ligand for 30 min followed by washout, the IC50 value of the mu-ligand was increased 2 fold whereas the IC50 value of the selective kappa-ligand was increased 32 fold and that of bremazocine 62 fold. Under these experimental conditions, it was shown that bremazocine is an antagonist against [D-Ala2,MePhe4,Gly-ol5]enkephalin at the mu-receptor (Ke = 1.6 nM). The residual agonist activity of bremazocine is at the kappa-receptor. In naive myenteric plexus preparations the mu-antagonist activity of bremazocine cannot be demonstrated because its potency at the kappa-receptor is very high. This dual action may be of importance for the responses of bremazocine in other peripheral and central tissues.

Topics: Animals; Benzomorphans; Electric Stimulation; Guinea Pigs; In Vitro Techniques; Morphinans; Myenteric Plexus; Naltrexone; Narcotic Antagonists; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

The effect of several mu and kappa opioid receptor agonists on rat plasma corticosterone levels, measured using radioimmunoassay, was investigated. The mu agonists, morphine and fentanyl, and the kappa agonists, U-50,488, tifluadom and bremazocine, all produced dose-related increases in rat plasma corticosterone levels. The effects of both fentanyl and U-50,488 were reversed by naloxone, indicating an action at opioid receptors. Pretreatment of the rats with the irreversible, mu-selective antagonist, beta-funaltrexamine, reduced the effect of fentanyl, but not that of U-50,488, indicating that both mu and kappa opioid receptors are involved in mediating this effect.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzodiazepines; Benzomorphans; Corticosterone; Dose-Response Relationship, Drug; Fentanyl; Male; Morphine; Naloxone; Naltrexone; Pyrrolidines; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

Topics: Animals; Benzomorphans; Cyclazocine; Diuresis; Ethylketocyclazocine; Naltrexone; Narcotics; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu