enkephalin--leucine-2-alanine and Substance-Related-Disorders

In addition to morphine-selective mu 2 and enkephalin-preferring delta sites, recent evidence supports the presence within the central nervous system of a common site with very high affinity for both enkephalins and opiates termed the mu 1 site. This concept of a common, very high affinity site for multiple neurotransmitters is a unique concept in neuropharmacology, differing from classical transmitter systems which possess multiple receptor classes for a single transmitter. This review will address both the biochemical and pharmacological evidence supporting the existence of this site.

Topics: Aging; Analgesia; Animals; Autoradiography; Binding, Competitive; Brain; Dihydromorphine; Endorphins; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Enkephalins; Ethylmaleimide; Morphine; Naloxone; Neurotransmitter Agents; Phylogeny; Receptors, Opioid; Receptors, Opioid, mu; Respiration; Substance-Related Disorders; Tissue Distribution

The mesolimbic dopamine system and cAMP-dependent/protein kinase A (PKA) pathways are strongly implicated in addictive behaviors. Here we determine the role of dopamine D2 receptors (D2) in PKA signaling responses to delta-opioid (DOR) and cannabinoid (CB1) receptors. We find in NG108-15/D2 cells and in cultured primary neurons that a brief exposure to saturating concentrations of DOR and CB1 agonists increases cAMP, promotes PKA C alpha translocation and increases cAMP-dependent gene expression. Activation of PKA signaling is mediated by Gi-beta gamma dimers. Importantly, subthreshold concentrations of DOR or CB1 agonists with D2 agonists, which are without effect when added separately, together activate cAMP/PKA signaling synergistically. There is also synergy between DOR or CB1 with ethanol, another addicting agent. In all instances, synergy requires adenosine activation of adenosine A2 receptors and is mediated by beta gamma dimers. Synergy by this molecular mechanism appears to confer hypersensitivity to opioids and cannabinoids while simultaneously increasing the sensitivity of D2 signaling when receptors are expressed on the same cells. This mechanism may account, in part, for drug-induced activation of medium spiny neurons in the nucleus accumbens.

Topics: Adenosine; Animals; Arachidonic Acids; Cell Line; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; Cyclic AMP-Dependent Protein Kinases; Dimerization; Dopamine Agonists; Drug Synergism; Enkephalin, Leucine-2-Alanine; Ethanol; GTP-Binding Protein beta Subunits; Isoenzymes; Models, Neurological; Neurons; Rats; Receptor, Cannabinoid, CB1; Receptors, Adenosine A2; Receptors, Opioid, delta; Substance-Related Disorders

Topics: Animals; Aorta, Thoracic; Cocaine; Cyclic AMP; Electric Stimulation; Guinea Pigs; Humans; Ileum; In Vitro Techniques; Male; Mice; Muscle, Smooth; Opioid-Related Disorders; Rats; Receptors, Dopamine; Receptors, Opioid; Receptors, Serotonin; Substance-Related Disorders

Previously, we have shown that the development of physical dependence on morphine in mice is inhibited substantially by treatment of mice with the highly selective, nonequilibrium delta-2 opioid receptor antagonist, naltrindole-5'-isothiocyanate. With the availability of the highly selective, nonequilibrium delta-1 opioid receptor antagonist, [D-Ala2,Leu5,Cys6]enkephalin, it was possible, in the present report, to examine the possible involvement of delta-1 opioid receptors in the development of opiate dependence. Mice were made physically dependent on morphine by s.c. implantation of morphine pellets (75-mg free base) for 3 days. The degree of dependence was quantified by determining the ED50 values of naloxone to precipitate withdrawal jumping and diarrhea. Neither sign of opiate withdrawal was affected by chronic treatment of animals with [D-Ala2,Leu5,Cys6]enkephalin during the morphine implant period. The data suggest that delta-1, as opposed to delta-2, opioid receptors are not involved in the development of physical dependence on morphine. This fact takes on added significance because the recently cloned delta opioid receptors appear to be the delta-2 subtype and the present data together with previous findings suggest that the cloned receptors may be proper models for the study of opiate dependence.

Topics: Affinity Labels; Animals; Diarrhea; Enkephalin, Leucine-2-Alanine; Injections, Intraventricular; Injections, Spinal; Isothiocyanates; Male; Mice; Morphine; Naloxone; Naltrexone; Receptors, Opioid, delta; Substance-Related Disorders

We previously showed that mouse sensory dorsal root ganglion (DRG) neurons chronically exposed to 1 microM D-ala2-D-leu5-enkephalin (DADLE) or morphine for > 2-3 days in culture become tolerant to the usual opioid inhibitory receptor-mediated effects, i.e. shortening of the duration of the calcium-dependent component of the action potential (APD), and supersensitive to opioid excitatory APD-prolonging effects elicited by low opioid concentrations. Whereas nanomolar concentrations of dynorphin(1-13) or morphine are generally required to prolong the APD of naive DRG neurons (by activating excitatory opioid receptors), femtomolar levels become effective after chronic opioid treatment. Whereas 1-30 nM naloxone or diprenorphine prevent both excitatory and inhibitory opioid effects but do not alter the APD of native DRG neurons, both opioid antagonists unexpectedly prolong the APD of most of the chronic opioid-treated cells. In the present study, chronic exposure of DRG neurons to 1 microM DADLE together with cholera toxin-B subunit (which selectively blocks GM1 ganglioside-regulated opioid excitatory, but not inhibitory, receptor functions) prevented the development of opioid excitatory supersensitivity and markedly attenuated tolerance to opioid inhibitory effects. Conversely, sustained exposure of DRG neurons to 1 nM DADLE, which selectively activates excitatory opioid receptor functions, resulted in characteristic opioid excitatory supersensitivity but no tolerance. These results suggest that 'dependence'-like properties can be induced in chronic opioid-treated sensory neurons in the absence of tolerance. On the other hand, development of some components of tolerance in these cells may require sustained activation of both excitatory, as well as inhibitory, opioid receptor functions.

Topics: Animals; Cholera Toxin; Drug Tolerance; Enkephalin, Leucine-2-Alanine; Ganglia, Spinal; Mice; Neurons, Afferent; Peptide Fragments; Receptors, Opioid; Sensitivity and Specificity; Substance-Related Disorders; Time Factors

The continuous intrathecal infusion of morphine (2, 6, 20 nmol/h), sufentanil (0.06, 0.2, 0.6 nmol/h), [D-Ala2,MePhe4, Gly-ol5]enkephalin (DAMGO) (0.1, 0.3, 1.0 nmol/h) or [D-Ala2,D-Leu5]enkephalin (DADLE) (2, 6, 20 nmol/h) in unanesthetized rats produces a dose-dependent increase in hot plate latency 1 day after pump implant followed by a gradual return to baseline values by days 3-4, i.e. tolerance. Rats assessed for opioid dependence after 7 days of intrathecal (i.t.) infusion of opioids show a withdrawal syndrome most readily noted by withdrawal body shakes (WBS) after injection of the opioid antagonist, naloxone (1 mg/kg i.p.). The number of WBS was proportional to the infusion dose of opioid agonist. Although each tolerance-producing agent was infused in one of three log-spaced (low, medium, high) doses, selected to have approximately equal antinociceptive activity across agents, the agents varied in the apparent degree of dependence. Thus, at the highest infusion dose, the average number of WBS observed was greatest for DADLE (32.8), morphine (30.2) and sufentanil (25.0) while animals treated with DAMGO displayed a significantly less degree of opioid dependence (8.7).

Topics: Animals; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Enkephalins; Fentanyl; Injections, Spinal; Male; Morphine; Naloxone; Narcotics; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Substance Withdrawal Syndrome; Substance-Related Disorders; Sufentanil; Time Factors

Topics: Adenosine; Adenylyl Cyclases; Animals; Cell Line; Clone Cells; Cytosol; Drug Tolerance; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Humans; Kinetics; Naloxone; Narcotics; Nerve Tissue Proteins; Substance-Related Disorders

Topics: Animals; Drug Tolerance; Endorphins; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Guinea Pigs; Humans; Hybrid Cells; Ileum; In Vitro Techniques; Male; Mice; Naloxone; Neurons; Receptors, Opioid; Substance-Related Disorders; Vas Deferens

Some in vivo agonist and antagonist properties of the putative k-compound bremazocine were characterized in rats. Bremazocine, at doses from 0.015-32 mg/kg i.p., delayed nociceptive reaction on a 55 degrees C hot-plate with a dose-response curve not readily fitting a single straight line; this effect was antagonized by high doses of naloxone. In the same rats bremazocine did not delay the intestinal transit of a charcoal meal fed 5 min earlier and prevented morphine-induced constipation. This antagonism appeared to be opioid-specific and competitive, with apparent pA2 value 8.56. Catatonia induced by etorphine (0.004 mg/kg s.c.) and constipation induced by etorphine (0.004 mg/kg s.c.) and D-Ala2-D-Leu5-enkephalin (0.1 mg/kg i.p.) were completely antagonized by bremazocine (0.03-8 mg/kg i.p.). Antinociception induced by morphine (10 mg/kg i.v.) and etorphine (0.004 mg/kg s.c.) was only partly prevented. Naloxone (1 mg/kg) and bremazocine (0.015-1 mg/kg i.p.) precipitated a withdrawal syndrome, evaluated as jumping frequency, in rats rendered dependent to morphine. These data suggest the involvement of more than one opioid receptor population in bremazocine action in vivo.

Topics: Analgesics; Animals; Benzomorphans; Catatonia; Constipation; Dose-Response Relationship, Drug; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Etorphine; Gastrointestinal Motility; Humans; Male; Morphinans; Morphine; Naloxone; Rats; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Animals; Dose-Response Relationship, Drug; Drug Tolerance; Electric Stimulation; Endorphins; Enkephalin, Leucine-2-Alanine; Enkephalins; Fentanyl; Humans; Male; Mice; Muscle Contraction; Muscle, Smooth; Receptors, Opioid; Substance-Related Disorders; Sufentanil; Vas Deferens