Opioid subtypes

The answer is c. (Hardman, pp 528-537.) Morphine is a pure agonist opioid drug with agonist activity toward all the opioid subtype receptor sites. In high doses, deaths associated with morphine are related to the depression of the respiratory center in the medulla. Morphine has a high addiction potential related to the activity of heroin or dihydromorphine. Codeine has a significantly lower addiction potential. 

In contrast, direct microinjection into brain parenchyma provided evidence of 6-opioid-mediated antinociception arising from supraspinal sites. In an early study aimed at determining the relative contribution of opioid subtypes to antinociception arising from different brain regions, morphine, DADLE, and ethylketocyclazocine (EKC) were microinjected directly into the PAG, NGC, and the NRM in the rat [109]. It was found that DADLE was more potent than morphine by 1 order of magnitude in the PAG and NRM, and less potent in the NGC [109], Furthermore, the potency of DADLE among these sites was consistent [109], In contrast, EKC was weakly active... 

Opiates iateract with three principal classes of opioid GPCRs )J.-selective for the endorphiQS,5-selective for enkephalins, and K-selective for dynorphias (51). AU. three receptors have been cloned. Each inhibits adenylate cyclase, can activate potassium channels, and inhibit A/-type calcium channels. The classical opiates, morphine and its antagonists naloxone (144) and naltrexone (145), have moderate selectivity for the. -receptor. Pharmacological evidence suggests that there are two subtypes of the. -receptor and three subtypes each of the 5- and K-receptor. An s-opiate receptor may also exist. 

The opioid peptides vary in their binding affinities for the multiple opioid receptor types. Leu- and Met-enkephalin have a higher affinity for 5-receptors than for the other opioid receptor types (68), whereas the dynorphin peptides have a higher affinity for K-sites (69). P-Endorphin binds with equal affinity to both p- and 5-receptors, but binds with lower affinity to K-sites (70). The existence of a P-endorphin-selective receptor, the S-receptor, has been postulated whether this site is actually a separate P-endorphin-selective receptor or is a subtype of a classical opioid receptor is a matter of controversy (71,72). The existence of opioid receptor subtypes in general is quite controversial although there is some evidence for subtypes of p- (73), 5-(74), and K-receptors (72,75), confirmation of which may be obtained by future molecular cloning studies. 

FIGURE 9.19 Dimeric antagonist formed by oligoglycyl-based linkage of two opioid receptor subtype antagonists naltrindole and ICI-199,441. From [59],... 

At present, no diugs exist that can selectively activate a2-receptor subtypes. Clonidine stimulates all three a2-subtypes with similar potency. Clonidine lowers blood pressure in patients with hypertension and it decreases sympathetic overactivity during opioid withdrawal. In intensive and postoperative care, clonidine is a potent sedative and analgesic and can prevent postoperative shivering. Clonidine and its derivative brimonidine lower... 

Opioids act on heptahelical G-protein-coupled receptors. Three types of opioid receptors (p, 8, k) have been cloned. Additional subtypes (e.g., pl3 p2, 81 82), possibly resulting from gene polymorphisms, splice variants or alternative processing have been proposed. Opioid receptors are localized and can be activated... 

The existence of further alternative transcripts of MOP was postulated by the observation that in knockout mice with disrupted exon 1, heroin but not morphine was still analgesically active. Based on earlier observations that the antagonist naloxazone blocked morphine-induced antinociception but not morphine-induced respiratory depression, a subdivision of the MOP in pi and p2 was proposed. However, no discrete mRNA for each of these MOP subtypes has been found. It is, however, possible that subtypes of MOPs result from heterodimerization with other opioid receptors or by interaction with other proteins. 

There is little new with regard to the mu receptor, the main target for opioid drugs. The receptor is remarkably similar in structure and function in all species studied so animal studies will be good predictors for clinical applications. Although there have been suggestions of subtypes of the receptor, the cloned mu receptors have all been identical. 

Figure 5.1 Visualization of the distribution of the DA transporter, D3 receptor, and K2-opioid receptor in the human brain of a drug-free control subject and a representative cocaine overdose victim. (A, B) The DA transporter was measured using [3H]WIN 35,428 (2 nM) as described previously. (C, D) The D3 receptor was measured using [3H]-(+)-7-OH-DPAT (1 nM) in the presence of GTP (300 m/W) to enhance the selective labeling of the D3 receptor subtype over the D2 receptor subtype as described previously. (E, F) The K2-opioid receptor subtype was measured using [125l]IOXY on tissue sections pretreated with BIT and FIT to occlude binding to the p- and 8-opioid receptors, respectively.

Rothman R., France C., Bykov V. et al. Pharmacological activities of optically pure enantiomers of the K opioid agonist, U50,488 and its els diastereomer evidence for three K receptor subtypes. Em J. Pharmacol. 167 345, 1989. 

Wollemann M., Benhye S., Simon J. The kappa-opioid receptor evidence for the different subtypes. Life Sci. 52 599, 1993. 

Nishi M., Takeshima H., Fukada K., Kato S., Mori K. cDNA cloning and pharmacological characterization of an opioid receptor with high affinities for kappa-subtype selective ligands. FEBS Lett. 330 77, 1993. 

Ni Q., Xu H., Partilla J. et al. Opioid peptide receptor studies. Interaction of opioid peptides and other drugs with four subtypes of the K2 receptor in guinea pig brain. Peptides. 16 1083, 1995. 

Self DW and Stein L (1992). Receptor subtypes in opioid and stimulant reward. Pharmacology and Toxicology, 70, 87-94. 

Sofuoglu M, Portoghese P, Takemori A. Differential antagonism of delta opioid agonists by naltrindole and its benzofuran analog (NTB) in mice evidence for delta opioid receptor subtypes. 

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