Inhibition of enkephalin metabolism and activation of mu- or delta-opioid receptors elicit opposite effects on reward and motility in the ventral mesencephalon

doi:10.1016/0028-3908(92)90179-S

Neuropharmacology

Volume 31, Issue 3, March 1992, Pages 293-298

https://doi.org/10.1016/0028-3908(92)90179-S Get rights and content

Abstract

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 intraeranial self-stimulation behaviour.

A greater increase in the rate of intraeranial 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 intraeranial 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.

References (28)

C.L. Broekkamp et al.
Facilitation of self-stimulation behaviour following intracerebral microinjections of opioids into the ventral tegmental area
Pharmac. Biochem. Behav.
(1979)
C.L. Broekkamp et al.
Separation of inhibiting and stimulating effect of morphine on self-stimulation behavior by intracerebral microinjections
Eur. J. Pharmac.
(1976)
Ph. De Witte et al.
Kelatorphan, a potent enkephalinases inhibitor, and opioid receptor agonists DAGO and DTLET, differentially modulate self-stimulation behaviour depending on the site of administration
Neuropharmacology
(1989)
K. Gysling et al.
Morphine-induced activation of A10 dopamine neurons in rat brain
Brain Res.
(1983)
D.W. Hommer et al.
The action of opiates in the rat substantia nigra: An electrophysiological analysis
Peptides
(1983)
F. Jenck et al.
Opioid receptor subtypes associated with ventral tegmental facilitation of lateral hypothalamic brain stimulation reward
Brain Res.
(1987)
R.P. Johnson et al.
A topographic localization of enkephalin on the dopamine neurons of the rat substantia nigra and ventral tegmental area demonstrated by combined histofluorescence-immunocytochemistry
Brain Res.
(1980)
E.M. Joyce et al.
The effects of morphine applied locally to mesencephalic dopamine cell bodies on spontaneous motor activity in the rat
Neurosci. Lett.
(1979)
R.T. Matthews et al.
Electrophysiological evidence for excitation of rat ventral tegmental area dopamine neurons by morphine
Neuroscience
(1984)
M.H. Weyers et al.
Two apparatus for detection of motility and water consumption of rodents
Physiol. Behav.
(1982)

R.A. Wise et al.

Brain substrates for reinforcement and drug self-administration

Prog. Neuropsychopharmac.

(1981)

G. Di Chiara et al.

Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats

G. Di Chiara et al.

Opposite effects of mu and kappa opiate agonists on dopamine-release in the nucleus accumbens and in the dorsal caudate of freely moving rats

J. Pharmac. exp. Ther.

(1988)

R.P. Dilts et al.

Localization of mu opioid and neurotensin receptors within the A₁₀ region of the rat

Ann. N.Y. Acad. Sci.

(1988)

Cited by (12)

Central D-Ala2-Met5-enkephalinamide μ/δ-opioid receptor activation blocks behavioral sensitization to cholecystokinin in CD-1 mice
2003, Brain Research
Citation Excerpt :
However, δ receptor activation in the accumbens shell modulates accumbal mesolimbic DA and CCK [96] which may influence the rewarding properties of VTA intracranial self-stimulation in mice. In non-stressed rats, intra-VTA injection of the selective μ and δ agonists, DAGO and DSTBULET, respectively, increased self-stimulation rates from the lateral hypothalamus [87] and the VTA [31], although DAGO increased VTA ICSS respective to DSTBULET [31]. The relative contributions of δ and μ receptor activation to motivated behaviour would be predicated on mesolimbic site-specific differences in receptor density as well as environmental stimuli which may modulate the release of variable neurotransmitter and neuropeptide systems with different affinities for the δ and μ receptor sub-types.
The present investigation revealed that intraventricular administration of the anxiogenic substance CCK-8S (50 ng) decreased responding for previously rewarding brain stimulation (intracranial self-stimulation; ICSS) and subsequently increased brain stimulation threshold determinations from the dorsal aspects of the ventral tegmental area (VTA) immediately following CCK administration. While central administration of the mixed μ/δ opioid receptor agonist d-Ala²-Met⁵-enkephalinamide (DALA; 1 μg) was ineffective in abrogating CCK induced ICSS deficits during the immediate post-stressor interval, DALA restored ICSS brain stimulation thresholds to basal values 24, 48 and 168 h following CCK challenge. At 18 days following the initial 50 ng CCK-8S and/or DALA challenges, mice were exposed to a previously determined non-anxiogenic dose of CCK-8S (5 ng). Among mice which received an intervening dose of saline following the 50 ng CCK-8S challenge, depressed ICSS responding and elevated brain stimulation thresholds were evident during the immediate (Day 18), 24- (Day 19) and 48-h (Day 20) test sessions relative to mice that received an intervening dose of DALA on Day 1. These data imply that while CCK induces relatively protracted and exaggerated behavioral disturbances, μ/δ opioid-receptor activation may block CCK-induced behavioral sensitization and change the course of psychopathology.
Inhibitors of Ca2+-dependent endopeptidases modulate morphine-induced effects in rats
1996, European Journal of Pharmacology
The effects of inhibitors of Ca²⁺-dependent endopeptidases (antipain and leupeptin) on morphine analgesia, reinforcing properties of morphine and on the development of opiate physical dependence were studied. Male Wistar rats were used. The analgesic action of morphine in the tail-immersion test was increased significantly by combined injection of morphine with antipain or leupeptin. Antipain or leupeptin alone had no analgesic action. The combination of morphine with antipain or leupeptin led to the reduction of morphine-induced place preference and the development of physical dependence. A single injection of antipain diminished the opiate-withdrawal signs in morphine-dependent rats. These results suggest a possible inhibitory effect of antipain or leupeptin on the Ca²⁺-dependent endopeptidases of neurons that mediate analgesia, reinforcing properties of morphine, development of opiate dependence and withdrawal.
Inhibitors of neprilysin: Design, pharmacological and clinical applications
1995, Methods in Enzymology
Endogenous opiates: 1992
1993, Peptides
This paper is the fifteenth installment of our annual review of research concerning the opiate system. It includes papers published during 1992 involving the behavioral, nonanalgesic, effects of the endogenous opiate peptides. The specific topics this year include stress; tolerance and dependence; eating; drinking; gastrointestinal and renal function; mental illness and mood; learning, memory, and reward; cardiovascular responses; respiration and thermoregulation; seizures and other neurological disorders; electrical-related activity; general activity and locomotion; sex, pregnancy, and development; immunological responses; and other behaviors.
Neurotransmitter regulation of dopamine neurons in the ventral tegmental area
1993, Brain Research Reviews
Over the last 10 years there has been important progress towards understanding how neurotransmitters regulate dopaminergic output. Reasonable estimates can be made of the synaptic arrangement of afferents to dopamine and non-dopamine cells in the ventral tegmental area (VTA). These models are derived from correlative findings using a variety of techniques. In addition to improved lesioning and pathway-tracing techniques, the capacity to measure mRNA in situ allows the localization of transmitters and receptors to neurons and/or axon terminals in the VTA. The application of intracellular electrophysiology to VTA tissue slices has permitted great strides towards understanding the influence of transmitters on dopamine cell function, as well as towards elucidating relative synaptic organization. Finally, the advent of in vivo dialysis has verified the effects of transmitters on dopamine and γ-aminobutyric acid transmission in the VTA. Although reasonable estimates can be made of a single transmitter's actions under largely pharmacological conditions, our knowledge of how transmitters work in concert in the VTA to regulate the functional state of dopamine cells is only just emerging. The fact that individual transmitters can have seemingly opposite effects on dopaminergic function demonstrates that the actions of neurotransmitters in the VTA are, to some extent, state-dependent. Thus, different transmitters perform similar functions or the same transmitter may perform opposing functions when environmental circumstances are altered. Understanding the dynamic range of a transmitter's action and how this couples in concert with other transmitters to modulate dopamine neurons in the VTA is essential to defining the role of dopamine cells in the etiology and maintenance of neuropsychiatrie disorders. Further, it will permit a more rational exploration of drugs possessing utility in treating disorders involving dopamine transmission.
An effective and safe enkephalin analog for antinociception
2021, Pharmaceutics

View all citing articles on Scopus

View full text

Article preview

Neuropharmacology

Abstract

References (28)

Facilitation of self-stimulation behaviour following intracerebral microinjections of opioids into the ventral tegmental area

Pharmac. Biochem. Behav.

Separation of inhibiting and stimulating effect of morphine on self-stimulation behavior by intracerebral microinjections

Eur. J. Pharmac.

Kelatorphan, a potent enkephalinases inhibitor, and opioid receptor agonists DAGO and DTLET, differentially modulate self-stimulation behaviour depending on the site of administration

Neuropharmacology

Morphine-induced activation of A10 dopamine neurons in rat brain

Brain Res.

The action of opiates in the rat substantia nigra: An electrophysiological analysis

Peptides

Opioid receptor subtypes associated with ventral tegmental facilitation of lateral hypothalamic brain stimulation reward

Brain Res.

A topographic localization of enkephalin on the dopamine neurons of the rat substantia nigra and ventral tegmental area demonstrated by combined histofluorescence-immunocytochemistry

Brain Res.

The effects of morphine applied locally to mesencephalic dopamine cell bodies on spontaneous motor activity in the rat

Neurosci. Lett.

Electrophysiological evidence for excitation of rat ventral tegmental area dopamine neurons by morphine

Neuroscience

Two apparatus for detection of motility and water consumption of rodents

Physiol. Behav.

Brain substrates for reinforcement and drug self-administration

Prog. Neuropsychopharmac.

Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats

Opposite effects of mu and kappa opiate agonists on dopamine-release in the nucleus accumbens and in the dorsal caudate of freely moving rats

J. Pharmac. exp. Ther.

Localization of mu opioid and neurotensin receptors within the A₁₀ region of the rat

Ann. N.Y. Acad. Sci.

Cited by (12)

Central D-Ala<sup>2</sup>-Met<sup>5</sup>-enkephalinamide μ/δ-opioid receptor activation blocks behavioral sensitization to cholecystokinin in CD-1 mice

Inhibitors of Ca<sup>2+</sup>-dependent endopeptidases modulate morphine-induced effects in rats

Inhibitors of neprilysin: Design, pharmacological and clinical applications

Endogenous opiates: 1992

Neurotransmitter regulation of dopamine neurons in the ventral tegmental area

An effective and safe enkephalin analog for antinociception

Inhibition of enkephalin metabolism and activation of mu- or delta-opioid receptors elicit opposite effects on reward and motility in the ventral mesencephalon

Abstract

Pharmac. Biochem. Behav.

Eur. J. Pharmac.

Neuropharmacology

Brain Res.

Peptides

Brain Res.

Brain Res.

Neurosci. Lett.

Neuroscience

Physiol. Behav.

Prog. Neuropsychopharmac.

Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats

Opposite effects of mu and kappa opiate agonists on dopamine-release in the nucleus accumbens and in the dorsal caudate of freely moving rats

J. Pharmac. exp. Ther.

Localization of mu opioid and neurotensin receptors within the A10 region of the rat

Ann. N.Y. Acad. Sci.

Localization of mu opioid and neurotensin receptors within the A₁₀ region of the rat