Bremazocine is an agonist at K‐opioid receptors and an antagonist at μ‐opioid receptors in the guinea‐pig myenteric plexus

Abstract

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 μ‐ or k‐opioid receptors were blocked preferentially. After pretreatment of the tissue with β‐funaltrexamine for 90 min followed by washing out, the IC50 value of the selective μ‐ligand [D‐Ala2,MePhe4,Gly‐ol5]enkephalin was increased 67 fold whereas the IC50 values of the selective k‐ligand U‐69,593 and of the non‐selective k‐ligand bremazocine were not significantly changed. In this experimental design bremazocine acted only on k‐receptors. After pretreatment of the tissue with β‐chlornaltrexamine and 10 μM of the μ‐ligand for 30 min followed by washout, the IC50 value of the μ‐ligand was increased 2 fold whereas the IC50 value of the selective k‐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 μ‐receptor (Ke. = 1.6 nM). The residual agonist activity of bremazocine is at the k‐receptor. In naive myenteric plexus preparations the μ‐antagonist activity of bremazocine cannot be demonstrated because its potency at the k‐receptor is very high. This dual action may be of importance for the responses of bremazocine in other peripheral and central tissues.

Acute withdrawal after bremazocine and the interaction between μ‐ and κ‐opioid receptors in isolated gut tissues

“…The observation that low concentrations of bremazocine determine a state of dependence in isolated preparations supports studies reporting the high potency and binding affinity of this drug to K-opioid receptors (Romer et al, 1980;Corbett & Kosterliz, 1986;Dissanayake et al, 1990). As with morphine and U-50,488H (Valeri et al, 1990a;Morrone et al, 1993) the use of low bremazocine concentrations makes it possible to obtain reproducible responses.…”

Pharmacological profile of various κ‐agonists at κ‐, μ‐ and δ‐opioid receptors mediating presynaptic inhibition of neurotransmitter release in the rat brain

“…The drugs examined were the benzomorphans bremazocine (Romer et al, 1980) and ethylketocyclazocine (EKC), the benzodiazepine analogue tifluadom (Romer et al, 1982) and the cyclohexyl benzeneacetamide derivatives U50488 (Von Voigtlander et al, 1983), U69593 (Lahti et al, 1985;Clark et al, 1988a) and PD1 17302 (Leighton et al, 1987;Clark et al, 1988b). Previous studies, investigating opioid agonist-induced inhibition of neurallyevoked contractions in smooth muscle preparations have shown that, in addition to acting as K-agonists, bremazocine and other benzomorphans may behave as 6-and/or p-opioid receptor antagonists (Gillan et al, 1981;McKnight et al, 1985;Corbett & Kosterlitz, 1986;Miller et al, 1986;Sheehan et al, 1986;Takemori et al, 1986). Ligand-receptor binding studies have revealed that bremazocine and other benzomorphan K-opioid agonists display quite high affinities for 6-and/or p-binding sites in the brain (Gillan & Kosterlitz, 1982;Paterson et al, 1983).…”

Analysis of the receptor specificity of tolerance induction in stress versus opioid-related prolactin secretion in rats

“…It is generally accepted that morphine exerts its opioid activity by preferential stimulation of the µ-receptor (Martin, 1967). On the other hand, bremazocine is accepted as a specificreceptor agonist, although it possesses an affinity for µ-and -receptors, resulting only in antagonism (Wood, Sanschagrin, Richard & Thakur, 1983;Petrillo, Gambino & Tavani, 1984;Corbett & Kosterlitz, 1986;Dunwiddie, Johnson & Proctor, 1987).…”