Action Of Opiate Drugs Research Articles

A Concise Review of Concepts in Opioid Pharmacology up to the Discovery of Endogenous Opioids.

This brief review covers concepts in opioid pharmacology that were promoted during the period leading up to the establishment of the International Narcotics Research Conference (INRC) in the early 1970s and the discovery of endogenous opioid peptides in 1975. The founders of INRC, meeting together during the International Union of Pharmacology meeting in Basel in 1969, recognized that the time was ripe for the creation of an international society that would provide a venue for the discussion of research across disciplines in this rapidly expanding area of science. The emphasis here is on studies leading to the demonstration that specific receptors for morphine-like analgesics exist, the search for endogenous ligands for these receptors, and early attempts to elucidate the mechanisms underlying opiate drug tolerance, dependence, and addiction. SIGNIFICANCE STATEMENT: Research on opioids in the 20th century was driven by the search for nonaddicting analgesics. This review discusses the development of the "analgesic" receptor concept, the demonstration that such receptors existed, and the search for an endogenous ligand. Conceptual models were proposed to explain tolerance to the actions of opiate drugs and the development of dependence and addiction. This review explains these models and indicates how they foreshadowed more recent discoveries on the acute and chronic actions of opiate drugs.

The stereoisomer (+)-naloxone potentiates G-protein coupling and feeding associated with stimulation of mu opioid receptors in the parabrachial nucleus

Classically, opioids produce their effects by activating Gi-proteins that inhibit adenylate cyclase activity. Previous studies proposed that mu-opioid receptors can also stimulate adenylate cyclase due to an initial transient coupling to Gs-proteins. Treatment with ultra-low doses of the nonselective opioid antagonist (-)-naloxone or its inactive enantiomer (+)-naloxone blocks this excitatory effect and enhances Gi-coupling. Previously we reported that infusion of the mu-opioid receptor agonist [D-Ala2, N-Me-Phe4, Glycinol5]-Enkephalin (DAMGO) into the mu-opioid receptor expressing lateral parabrachial nucleus increases feeding. Pretreatment with (-)-naloxone blocks this effect. We used this parabrachial circuit as a model to assess cellular actions of ultra-low doses of (-)-naloxone and (+)-naloxone in modifying the effects of DAMGO. Our results showed that an ultra-low concentration of (-)-naloxone (0.001 nM) and several concentrations of (+)-naloxone (0.01-10 nM) enhanced DAMGO-stimulated guanosine-5'-0-(γ-thio)-triphosphate incorporation in parabrachial sections in vitro. Further, we analyzed the relevance of these effects in vivo. In the present study, we show that (+)-naloxone can potentiate DAMGO-induced feeding at doses at which (-)-naloxone was an antagonist. These results implicated (+)-naloxone as a novel tool for studying mu-opioid receptor functions and suggest that (+)-naloxone may have therapeutic value to enhance clinical actions of opiate drugs.

Recent Developments in the Study of Opioid Receptors

It is now about 40 years since Avram Goldstein proposed the use of the stereoselectivity of opioid receptors to identify these receptors in neural membranes. In 2012, the crystal structures of the four members of the opioid receptor family were reported, providing a structural basis for understanding of critical features affecting the actions of opiate drugs. This minireview summarizes these recent developments in our understanding of opiate receptors. Receptor function is also influenced by amino acid substitutions in the protein sequence. Among opioid receptor genes, one polymorphism is much more frequent in human populations than the many others that have been found, but the functional significance of this single nucleotide polymorphism (SNP) has been unclear. Recent studies have shed new light on how this SNP might influence opioid receptor function. In this minireview, the functional significance of the most prevalent genetic polymorphism among the opioid receptor genes is also considered.

Haplotype block structure of the genomic region of the mu opioid receptor gene

The opioid system is involved in the action of opiate drugs, opioid addiction, pain experience and analgesia. Individual differences in opioid effect may be attributed in part to genetic variations. Long-range cis regulatory elements and intronic variants are potential sources of functional diversity. Recently, we have detected association of two intronic OPRM1 variants with heroin addiction in European Americans. In the current study, we analyzed the genetic variations in the OPRM1 100 kb 5′ flanking region and intron 1 in the HapMap Caucasian population. Four major linkage disequilibrium (LD) blocks were identified, consisting of 28, 22, 15 and 42 SNPs, respectively. The locations of these blocks are (−100 – −90), (−90 – −67), (−20 - −1) and (+1 – +44) kb, respectively. The two intronic variants, indicated in our recent study, are part of a distinct haplogroup that include SNPs from intron 1, and the proximal 5′ region. The 118G (rs1799971) allele is part of a different haplogroup that includes several variants in the distal 5′ region that may have a regulatory potential. These findings were corroborated by genotyping eight SNPs in a sample of European Americans and suggest an extended OPRM1 locus with potential new regulatory regions.

Overview and historical perspective of four papers presented on research related to the endogenous opioid system

Overview and historical perspective of four papers presented on research related to the endogenous opioid system

Brain Region Specific Actions of Regulator of G Protein Signaling 4 Oppose Morphine Reward and Dependence but Promote Analgesia

Regulator of G protein signaling 4 (RGS4) is one of the smaller members of the RGS family of proteins, which are known to control signaling amplitude and duration via interactions with G protein alpha subunits or other signaling molecules. Earlier evidence suggests dynamic regulation of RGS4 levels in neuronal networks mediating actions of opiates and other drugs of abuse, but the consequences of RGS4 actions in vivo are largely unknown. In this study, we use constitutive and nucleus accumbens-inducible RGS4 knockout mice as well as mice overexpressing RGS4 in the nucleus accumbens via viral mediated gene transfer, to examine the influence of RGS4 on behavioral responses to opiates. We also use electrophysiology and immunoprecipitation assays to further understand the mechanisms underlying the tissue-specific actions of RGS4. Inducible knockout or selective overexpression of RGS4 in the nucleus accumbens reveals that, in this brain region, RGS4 acts as a negative regulator of morphine reward, whereas in the locus coeruleus RGS4 opposes morphine physical dependence. In contrast, we show that RGS4 does not affect morphine analgesia or tolerance but is a positive modulator of certain opiate analgesics, such as methadone and fentanyl. These findings provide fundamentally novel information concerning the role of RGS4 in the cellular mechanisms underlying the diverse actions of opiate drugs in the nervous system.

Circulating met-enkephalin in trained athletes during rest, exhaustive treadmill exercise and marathon running

Twelve trained male athletes were subjected to a progressive intensity treadmill exercise test to total exhaustion and at a later date took part in the Comrades Marathon. Blood was taken in order to determine whether plasma met-enkephalin levels increase in an exercise-intensity dependent manner. The mean concentrations in f mol/ml were as follows: post-exercise levels (266) were significantly higher than basal levels (172), and the post-marathon levels (378) rose significantly above the post-exercise levels. The magnitude of the responses is thus correlated with the amount of work performed and would suggest that this opioid peptide is involved in physiological actions that perhaps extend beyond the pharmacological actions of opiate drugs.

Neonatal monosodium glutamate administration alters noradrenergic measures in the brainstem of the mouse

Mice treated neonatally with MSG (4 mg/g) were compared to saline-injected controls on a number of neurochemical parameters of brainstem noradrenergic activity. MSG treatment resulted in an attenuation of brainstem norepinephrine (NE) decline after α-methyl-p-tyrosine administration. Neonatal MSG administration did not result in alterations in the steady state levels of brainstem NE or MOPEG. The synthesis of NE was slightly increased in the pons-medulla of MSG-treated mice as indexed by pargyline-induced NE accumulation. NE release, however, appeared diminished as reflected by a significant ( p < 0.05) decrease in the ratio of normetanephrine to NE found in the pons-medulla of MSG-treated mice given pargyline. The results suggest that MSG-induced damage to the arcuate nucleus produces selective alterations in brainstem NE systems. These alterations may reflect the toxic action of MSG on the opiomelanocortin neurons of the arcuate nucleus or other descending systems that are damaged by MSG. The loss of the descending opiomelanocortin input to the brainstem could result in these types of neurochemical consequences since the pharmacologie action of opiate drugs results in a selective enhancement of brainstem NE turnover in rodents.

Studies of the mechanism of the antidiarrheal effect of codeine.

To determine whether the antidiarrheal action of opiate drugs in humans is due to enhanced intestinal absorption rates, as suggested by recent experiments in animals, or is due to altered intestinal motility, as traditionally thought, we studied the effect of therapeutic doses of codeine on experimental diarrhea and on the rate of intestinal absorption of water and electrolytes in normal human subjects. Our results show that codeine (30-60 mg i.m.) markedly reduced stool volume during experimental diarrhea induced by rapid intragastric infusion of a balanced electrolyte solution. There was, however, no evidence that codeine stimulated the rate of intestinal absorption in the gut as a whole or in any segment of the gastrointestinal tract, either in the basal state or when absorption rates were reduced by intravenous infusion of vasoactive intestinal polypeptide. We also measured segmental transit times to determine whether and where codeine delayed the passage of fluid through the intestine. Codeine caused a marked slowing of fluid movement through the jejunum, but had no effect on the movement of fluid through the ileum or colon. In other studies, we found that the opiate antagonist naloxone did not significantly affect water or electrolyte absorption rates in the jejunum or ileum. We conclude (a) that therapeutic doses of codeine increase net intestinal absorption (and thereby reduce stool volume) by increasing the contact time of luminal fluid with mucosal cells, not by increasing the rate of absorption by the mucosal cells; and (b) that endogenous opiates do not regulate intestinal absorption in humans.

Immunohistochemical mapping of enkephalin containing cell bodies, fibers and nerve terminals in the brain stem of the rat

Enkephalin immunoreactive perikarya, fibers and nerve terminals, visualized by the indirect immunohistofluorescent method in colchicine-pretreated animals, are localized in many discrete regions of the rat brain stem. These specific immunohistofluorescent patterns are similar after staining with selective primary antisera directed against either methione-enkephalin or leucine-enkephalin. Cell bodies are found in the substantia gelatinosa and interpolaris zones of the trigeminal nuclear complex, the nucleus of the solitary tract, in the vicinity of the nucleus raphe´magnus, in the dorsal cochlear, medial vestibular, and paraolivary nuclei and, dorsal to this last region, in the parabrachial nuclei and the dorsal tegmental nucleus of Gudden, in the periaqueductal gray matter and interpeduncular nucleus and along the borders of the lateral lemniscus and medial geniculate. In some areas, such as the parabrachial region, nucleus of the solitary tract and substantia gelatinosa of the trigeminal nucleus, these perikarya are associated with densities of fibers and terminals. Other regions, such as the dorsal cochlear nucleus and the vicinity of the nucleus raphe´magnus, contain cell bodies associated with low densities of processes and terminals. In still other nuclei, such as the nucleus of the facial nerve and the locus coeruleus, fiber and terminal densities without associated cell bodies are evident. Many of these enkephalin localizations can be rationalized on the basis of known actions of opiate drugs and the brain stem distribution of opiate receptors.

Stimulant effects of enkephalin microinjection into the dopaminergic A10 area

THE overt behaviour of various species is affected in different ways by opiate drugs. Mice and cats show behavioural stimulation following a systemic morphine injection whereas rats and dogs generally exhibit decreased behavioural activity1–4, although in certain conditions, stimulant effects can also be seen in the latter species4,5. Tatum et al. suggested that there are several distinct sites of action of opiate drugs in brain and that the relative dominance of one system over another determines whether the stimulant or depressant effects predominate4. Indeed, direct microinjections of morphine into the ventral tegmental area (VTA) have been shown to result in facilitation of self-stimulation behaviour whereas similar injections into the periaqueductal gray matter cause only an attenuation of this behaviour6. The discovery of endogenous ligands for opiate receptors in the brain7 has focused attention on the role of these peptides in various aspects of behaviour. Their analgesic properties following intr a ventricular and intracerebral injection are well documented8. Recently, it has been reported that infusion of α-endorphin into the substantia nigra induced stereotyped behaviour9, whereas local injections into the nucleus accumbens of the long-acting synthetic enkephalin analogue, [D-Ala2]-Met5-enkephalinamide (AME), produced an increase in locomotor activity10. We now report that infusion of AME (0.03–2.0 µg) bilaterally into the dopaminergic (DA) A10 area of the VTA induces a short-latency behavioural stimulant effect reminiscent of effects produced by stimulation of the mesolimbic DA pathway11. This effect is antagonised by pretreatment with the opiate receptor blocker naloxone.