enkephalin--ala(2)-mephe(4)-gly(5)- and kelatorphan

Patients receiving opioids report feeling sleepy, but opioids actually inhibit the rapid eye movement phase of sleep (REM). Inhibition of REM sleep is followed by a rebound increase in REM sleep associated with cardiopulmonary complications. The medial pontine reticular formation (mPRF) is a brain region from which morphine can inhibit REM sleep. The present study tested the hypothesis that specific subtypes of opioid receptors within the mPRF mediate inhibition of REM sleep. Synthetic opioid agonists selective for mu, delta and kappa subtypes were microinjected into the mPRF of four awake cats and polygraphic recordings of sleep and breathing were obtained. An enkephalinase inhibitor was microinjected into the mPRF to assess the contribution of endogenous opioids to the control of sleep and breathing. Only the mu agonist significantly inhibited REM sleep, and no opioid depressed breathing. These results demonstrate that opioid-induced REM sleep inhibition is mediated by mu receptor subtypes in the mPRF.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Cats; Dipeptides; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Male; Neprilysin; Pyrrolidines; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Respiration; Reticular Formation; Sleep, REM; Wakefulness

The coexistence of endogenous opioid systems and dopaminergic neurones in the midbrain tegmental area suggests functional interactions between dopamine and enkephalins. Nevertheless, the identification of the specific opioid receptors associated with modulation of tegmental dopamine activity and its behavioural concomitants on motility and reward is far from clear, considering the mixed nature of the ligands usually employed. In this way, kelatorphan, a potent inhibitor of enkephalinases and selective agonists for mu- and delta-opioid receptor subtypes (DAGO and DSTBULET, respectively) were infused directly into the ventral tegmental area of the rat to study the role of endogenous enkephalins and opioid receptors in regulating spontaneous motor activity and intracranial self-stimulation behaviour. A greater increase in the rate of intracranial self-stimulation behaviour was found after activation of mu-opioid receptors in the ventral tegmental area, as compared to activation of delta-opioid receptors, whereas enhancement of endogenous enkephalins by inhibiting their metabolism through kelatorphan, reduced the rate of intracranial self-stimulation behaviour. On the contrary, spontaneous motor activity was reduced by the delta-opioid receptor agonist, whereas kelatorphan increased the movements of the animal. Taken together, these results show that inhibition of the metabolism of enkephalins in the ventral tegmental area decreased positive reinforcement from the lateral hypothalamic medial forebrain bundle and increased spontaneous movements. On the contrary, activation of both mu- or delta-opioid receptors in the ventral tegmental area significantly increased self-stimulation and decreased spontaneous motor activity, supporting the view that different mechanisms underlie the behavioural effects, resulting from enhancement of endogenous enkephalins and from activation of specific opioid receptors in the ventral mesencephalon.

Topics: Animals; Brain; Dipeptides; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Male; Mesencephalon; Motor Activity; Oligopeptides; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Reward; Self Stimulation

Lesioning of dopamine neurons by injection of 6-hydroxydopamine into the nucleus accumbens blocked the increased rearing activity measured in the open-field and induced by injection into the ventral tegmental area of: [R)-3-(N-hydroxylcarboxamido-2-benzyl-propanoyl)-L-alanine), kelatorphan (complete inhibitor of enkephalin catabolism) or by (Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr(OtBu)): BUBU (selective delta agonist) but not the hypolocomotion evoked by the mu agonist (Tyr-D-Ala-Gly-N(Me)-Phe-Glyol): DAMGO. This suggests the involvement of different neuronal pathways in mu and delta effects.

Topics: Amino Acid Sequence; Analgesics; Animals; Behavior, Animal; Dipeptides; Dopamine; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Limbic System; Male; Molecular Sequence Data; Motor Activity; Neurons; Nucleus Accumbens; Oligopeptides; Oxidopamine; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Tegmentum Mesencephali

Topics: Animals; Dipeptides; Dopamine; Endorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Hydroxydopamines; Limbic System; Male; Motor Activity; Oxidopamine; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu

We have previously (Daugé et al. 1988) demonstrated that injection of the mu agonist [D-Ala2, MePhe4, Gly-ol5]-enkephalin (DAGO) or the delta agonist [D-Thr2, Leu5]-enkephalyl-Thr6 (DTLET) into the rat Nucleus accumbens (N.Acc.), or Nucleus caudatus (N.Caud.) induced a hypoactivity followed by hyperactivity 150 min later in the case of the mu agonist and a hyperactivity in the case of the delta agonist. Moreover, naloxone reversible delta-type responses were obtained by local infusion of kelatorphan, ([(R)-3(N-hydroxylcarboxamido-2-benzylpropanoyl)-L-alanine]), a complete inhibitor of enkephalin catabolism, suggesting a tonic control of the behavioral activity of rat by the endogenous opioid peptides. In this work, the putative involvement of the dopaminergic system in these behavioral responses was investigated by using the DA antagonist thioproperazine. In the N.Acc., the behavioral effects of kelatorphan or of mu or delta agonists were not altered by thioproperazine-induced blockade of dopamine receptors. In contrast, the hyperactivity produced by DTLET or by kelatorphan in the N.Caud. was reversed by thioproperazine while the time-dependent biphasic effect resulting from DAGO injection remained unaffected by the DA antagonist. This blocking effect of thioproperazine is in agreement with the previously described delta-selective enhancement of the release of newly synthesized DA in the striatum but not in the N.Acc.

Topics: Animals; Apomorphine; Behavior, Animal; Caudate Nucleus; Dipeptides; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Male; Microinjections; Motor Activity; Nucleus Accumbens; Oligopeptides; Phenothiazines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Septal Nuclei

Endogenous enkephalins have been found in the perikaryon of the mesolimbic dopaminergic ventral tegmental area and in axonal terminals in the nucleus accumbens. To examine whether endogenous opioid peptides may modulate this mesolimbic system, injections of dopamine receptor agonists and antagonist, the mu-opioid receptor agonists DAGO and morphine, the delta-opioid receptor agonist DTLET and kelatorphan, a new potent inhibitor of multiple enkephalin-degrading enzymes, were performed into the lateral ventricle and into the nucleus accumbens. Intracranial self-stimulation behaviour, obtained through electrodes chronically implanted into the medial forebrain bundle in the posterolateral hypothalamus of the rat, was used as behavioural paradigm. Injections of kelatorphan and DTLET into the lateral ventricle both induced an ICI 174,864-reversible increased self-stimulation behaviour, a similar increase was observed after injection of d-amphetamine, while morphine and DAGO reduced the rate of self-stimulation. In contrast, the administration of kelatorphan or dopamine receptor agonists into the nucleus accumbens reduced the rate of intracranial self-stimulation, while DTLET was without effect, when injected into the same structure. Finally, intra-accumbens injections of DAGO produced a similar behavioural profile to that produced by intraventricular injections of the drugs. Opioids may thus differentially affect intracranial self-stimulation behaviour, as a function of the neuroanatomical locus of administration. Furthermore, these results suggest that kelatorphan may increase self-stimulation behaviour through an action at delta-opioid receptor, while DAGO and morphine may reduce self-stimulation behaviour through an action at mu-opioid receptors.

Topics: Animals; Behavior, Animal; Dextroamphetamine; Dipeptides; Electrodes, Implanted; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalins; Injections; Injections, Intraventricular; Male; Neprilysin; Nucleus Accumbens; Oligopeptides; Rats; Rats, Inbred Strains; Self Stimulation

The effects of selective agonists for delta opioid receptors: [D-Thr2, Leu5]-enkephalyl-Thr6 (DTLET) and mu receptors: [D-Ala2, MePhe4, Gly-ol5]-enkephalin (DAGO) and of (R)-3-(N-hydroxyl-carboxamido-2-benzylpropanoyl)-L-alanine (kelatorphan), a complete inhibitor of enkephalin degrading enzymes, on the motor activity of rats was examined after their local administration into the nucleus accumbens (NA) or nucleus caudatus (NC). In both structures DTLET dose dependently enhanced locomotor activity as measured in the open-field test. This strong effect was reversed by the selective delta antagonist: ICI 174,864. Contrastingly, DAGO induced hypoactivity followed by hyperactivity 150 min later. This biphasic effect was blocked by systemic injection of naloxone, but not by ICI 174,864. The physiological relevance of these effects was ascertained by the naloxone-reversible stimulatory responses induced by kelatorphan, supporting a role for endogenous enkephalins in the control of behavior through delta receptor stimulation.

Topics: Animals; Behavior, Animal; Caudate Nucleus; Dipeptides; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Male; Motor Activity; Naloxone; Neprilysin; Norepinephrine; Nucleus Accumbens; Oligopeptides; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu

The effects of the specific delta-agonist of opiate receptors, DTLET (Tyr-D-Thr-Gly-Phe-Leu-Thr), the specific mu-agonist DAGO (Tyr-D-Ala-Gly-(Me)Phe-Gly-ol) and of kelatorphan (N-((2R)-3-(hydroxyaminocarbonyl-2-benzyl-1-oxopropyl)-L-alanine), a potent inhibitor of the enkephalin-degrading enzymes, on the spontaneous release of [3H]dopamine ([3H]DA) synthesized from [3H]tyrosine were examined in rat striatal slices. DTLET (10(-7) M, 10(-6) M) and kelatorphan (5 X 10(-6) M) enhanced markedly the release of newly synthesized [3H]DA, while DAGO (10(-6) M) was inactive. The stimulatory effects of DTLET (10(-7) M) and kelatorphan (5 X 10(-6) M) were prevented in the presence of naloxone (3 X 10(-6) M; 10(-4) M respectively) or ICI 154,129 (10(-5) M), a selective antagonist of delta-opiate receptors. While DTLET (10(-7) M) stimulated the 30 mM potassium-evoked release of newly synthesized [3H]DA, it did not affect the potassium-evoked release of [3H]DA previously synthesized in tissues. A higher concentration of DTLET (10(-6) M) was required in the latter case. In contrast to the release observed with striatal slices, DTLET (10(-7) M), 10(-6) M) or DAGO (10(-6) M) did not affect the spontaneous release of newly synthesized [3H]DA from nucleus accumbens slices. In addition, DTLET (10(-6) M) was without effect on the potassium-evoked release of newly synthesized [3H]DA in this structure. The present results confirmed that delta-opiate receptors are involved in the presynaptic regulation of [3H]DA release.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Corpus Striatum; Dipeptides; Dopamine; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; In Vitro Techniques; Male; Nucleus Accumbens; Oligopeptides; Potassium; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, mu; Synapses

Kelatorphan, a full inhibitor of aminopeptidases, enkephalinase and dipeptidylaminopeptidase, enzymes which degrade the enkephalins, produced inhibitions (around 50%) of dorsal horn C fibre evoked responses in the rat, following local application. The inhibitions were reversed by the selective delta-opiate receptor antagonists ICI 174,864. Furthermore the inhibitions produced by two doses of Tyr-D-Ala-Gly-MePhe-Gly-ol (DAGO), a potent selective mu-opiate receptor agonist, were not altered in the presence of kelatorphan, so demonstrating an additive effect of the mu-agonist and the enzyme inhibitor. The inhibitions produced by the enzyme inhibitor would seem due to an increased availability of endogenous opioids, presumably the enkephalins which act via the delta-opiate receptor.

Topics: Animals; Dipeptides; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine; Enkephalins; Nerve Fibers; Neural Inhibition; Rats; Receptors, Opioid; Receptors, Opioid, delta; Spinal Cord