enkephalin--ala(2)-mephe(4)-gly(5)- and Brain-Injuries

Discrete midline lesions uncouple left and right respiratory motor output in mammals, but not in frogs and lampreys. To address this question in reptiles, isolated adult turtle brainstems were cut along the midline while recording respiratory motor output (bursts of action potentials) on left and right hypoglossal (XII) nerves. XII motor bursts were synchronized as long as a small portion of the midline was still intact. When turtle brainstems were completely cut along the midline and separated into hemibrainstems, XII motor bursts were produced that could be abolished by mu-opioid receptor (MOR) activation or exposure to high pH (7.80) solution. Also, 13/57 hemibrainstems expressed episodic discharge (>1.75bursts/episode). To test whether crossed connections were necessary to express a long-lasting increase in burst frequency (i.e., frequency plasticity), phenylbiguanide (PBG, 5-HT(3) receptor agonist, 20microM) was bath-applied to hemibrainstems. Although PBG significantly increased burst frequency by 0.43+/-0.10bursts/min after 60min, no frequency plasticity was observed because burst frequency returned to near baseline levels after a 2-h washout. Thus, crossed connections in turtle brainstems synchronize respiratory motor output and are not required for normal respiratory pattern formation, but are required for PBG-dependent frequency plasticity.

Topics: Action Potentials; Analgesics, Opioid; Animals; Biguanides; Brain Injuries; Brain Stem; Dose-Response Relationship, Drug; Electrophysiology; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Functional Laterality; Hydrogen-Ion Concentration; In Vitro Techniques; Respiration; Respiratory Center; Serotonin Receptor Agonists; Time Factors; Turtles

Information processing within the striatum is regulated by local circuits involving dopamine, cholinergic interneurons and neuropeptides released by recurrent collaterals of striatal output neurons. In the limbic-prefrontal territory of the dorsal striatum, enkephalin inhibits the NMDA-evoked release of acetylcholine directly through micro-opioid receptors (MORs) located on cholinergic interneurons and indirectly through MORs of output neurons of striosomes. In this territory, we investigated the consequence of changes in dopamine transmission, bilateral 6-hydroxydopamine-induced degeneration of striatal dopaminergic innervation or cocaine (acute and chronic) exposure on (i) MOR expression in both cholinergic interneurons and output neurons of striosomes, and (ii) the direct and indirect enkephalin-MOR regulations of the NMDA-evoked release of acetylcholine. Expression of MORs in cholinergic interneurons was preserved after 6-hydroxydopamine and down-regulated after cocaine treatments. Accordingly, the direct enkephalin-MOR control of acetylcholine release was preserved after 6-hydroxydopamine treatment and lost after cocaine exposure. Expression of MORs in output neurons of striosomes was down-regulated in the 6-hydroxydopamine situation and either preserved or up-regulated after acute or chronic cocaine exposure, respectively. Accordingly, the indirect enkephalin-MOR control of acetylcholine release disappeared in the 6-hydroxydopamine situation but surprisingly, despite preservation of MORs in striosomes, disappeared after cocaine treatment. Showing that MORs of striosomes are still functional in this situation, the MOR agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin inhibited the NMDA-evoked release of acetylcholine after cocaine exposure. Therefore, alteration in the regulation of cholinergic transmission by the enkephalin-MOR system might play a major role in the motivational and cognitive disorders associated with dopamine dysfunctions in fronto-cortico-basal ganglia circuits.

Topics: Acetylcholine; Animals; Behavior, Animal; Brain Injuries; Circadian Rhythm; Cocaine; Corpus Striatum; Dopamine Uptake Inhibitors; Drug Administration Schedule; Drug Interactions; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Excitatory Amino Acid Agonists; Functional Laterality; Male; Models, Neurological; N-Methylaspartate; Oxidopamine; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Tritium

We examined the effects of an exogenous mu opioid agonist and antagonist on systemic physiology and neurological outcome following TBI in the rat. Experiment I: [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) (0.1 nMol or 0.3 nMol in 5 microliters) (n = 10) or artificial CSF (n = 10) was administered 5 min prior to fluid-percussion brain injury (2.1 atmospheres). Motor performance was assessed on days 1-5 after TBI. The mu receptor agonist, DAMGO significantly reduced both beam-walking latency and body weight loss after injury (p < 0.05). DAMGO-treated rats (n = 5) did not differ from CSF-treated rats (n = 5) on either systemic arterial blood pressure or heart rate responses to injury. Experiment II: Beta-funaltrexamine (beta-FNA) (20.0 nMol in 5.0 microliters) (n = 10) or artificial CSF (n = 10) was administered (icv) to rats 5 min prior to fluid-percussion brain injury (1.8 atmospheres). Motor performance was assessed on days 1-5 after TBI. The mu receptor antagonist, beta-FNA, significantly increased beam-walking latency after injury (p < 0.05). beta-FNA-treated rats (n = 5) did not differ from CSF-treated rats (n = 5) on either systemic arterial blood pressure or heart rate responses to injury. Experiment III: Neither beta-FNA nor DAMGO affected motor performance in uninjured rats. These results suggest that activation of mu opioid receptors by exogenous agonists may provide protection against deficits in motor performance produced by fluid percussion brain injury.

Topics: Animals; Brain Injuries; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Male; Naltrexone; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu; Treatment Outcome

We have recently demonstrated that [3H]ohmefentanyl, a non-peptidergic opioid ligand which was suggested to cross the blood brain barrier in contrast to other peptidergic opioid ligands, bound not only to mu opioid receptor sites but also to sigma sites. In order to examine whether [3H]ohmefentanyl can be used as a marker for mu sites, we investigated the effects of brain lesions on [3H]ohmefentanyl binding site densities, as compared with [3H][D-Ala2, MePhe4, Gly-ol5]enkephalin ([3H]DAGO), a selective mu ligand. These binding site densities were measured by quantitative autoradiography in the rat striatum and substantia nigra, two brain structures known to contain a high density of mu receptors, following lesions of the nigro-striatal dopaminergic pathway and striatal intrinsic neurons. Following unilateral nigral lesion with 6-hydroxydopamine, [3H]ohmefentanyl binding site densities were decreased in the patches (-35%) and matrix (-20%) of the ipsilateral striatum and in the lesioned substantia nigra pars compacta (-49%). Unilateral striatal lesion with quinolinic acid induced 72%, 61% and 50% decreases in [3H]ohmefentanyl binding in the patches and matrix of the lesioned striatum and in the ipsilateral substantia nigra pars reticulata, respectively. Similar results were obtained in the binding of [3H]DAGO. Indeed, a significant linear correlation was observed between [3H]ohmefentanyl and [3H]DAGO binding site densities. Therefore, mu opioid receptors may be mainly located on intrinsic neurons in the striatum, dopaminergic cell bodies in the substantia nigra pars compacta and nerve terminals of striatal efferents in the substantia nigra pars reticulata.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain Injuries; Corpus Striatum; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Fentanyl; Male; Rats; Rats, Wistar; Receptors, Opioid; Substantia Nigra