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

Abstract

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.