heroin and eticlopride

Mu opioid receptor agonists such as morphine stimulate the release of dopamine (DA) in various brain regions. These increases in DA are thought to be involved in some of the behavioral effects of mu agonists. The present study was designed to examine the modulatory actions of two D2/3 antagonists (nafadotride and eticlopride), the D2/3 partial agonist BP897, the D1/2 antagonist flupenthixol, and the D1 antagonist SCH23390 on the discriminative stimulus effects of the mu partial agonist nalbuphine and the higher-efficacy mu agonists heroin, methadone and morphine, in rats trained to discriminate heroin from water. Both nafadotride and eticlopride attenuated the effects of the mu agonists, whereas BP897 was effective against nalbuphine and partially effective against morphine. Flupenthixol attenuated the heroin-like discriminative stimulus effects of heroin and morphine, although not as completely as nafadotride or eticlopride. SCH23390 was least effective and produced little attenuation. These results demonstrate that the discriminative stimulus effects of mu agonists in rats are more readily attenuated by drugs that block D2-like, rather than D1-like, receptors.

Topics: Animals; Benzazepines; Brain; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Flupenthixol; Heroin; Methadone; Morphine; Motivation; Nalbuphine; Naphthalenes; Piperazines; Pyrrolidines; Rats; Rats, Long-Evans; Receptors, Dopamine D1; Receptors, Dopamine D3; Receptors, Opioid, mu; Salicylamides

The periaqueductal grey (PAG) area is involved in pain modulation as well as in opiate-induced anti-nociceptive effects. The PAG possess dopamine neurons, and it is likely that this dopaminergic network participates in anti-nociception. The objective was to further study the morphology of the PAG dopaminergic network, along with its role in nociception and opiate-induced analgesia in rats, following either dopamine depletion with the toxin 6-hydroxydopamine or local injection of dopaminergic antagonists. Nociceptive responses were studied through the tail-immersion (spinal reflex) and the hot-plate tests (integrated supraspinal response), establishing a cut-off time to further minimize animal suffering. Heroin and morphine were employed as opiates. Histological data indicated that the dopaminergic network of the PAG is composed of two types of neurons: small rounded cells, and large multipolar neurons. Following dopamine depletion of the PAG, large neurons (not small ones) were selectively affected by the toxin (61.9% dopamine cell loss, 80.7% reduction of in vitro dopaminergic peak), and opiate-induced analgesia in the hot-plate test (not the tail-immersion test) was reliably attenuated in lesioned rats (P < 0.01). After infusions of dopaminergic ligands into the PAG, D(1) (not D(2)) receptor antagonism attenuated opiate-induced analgesia in a dose-dependent manner in the hot-plate test. The present study provides evidence that large neurons of the dopaminergic network of the PAG participate in supraspinal (not spinal) nociceptive responses after opiates through the involvement of D(1) dopamine receptors. This dopaminergic system should be included as another network within the PAG involved in opiate-induced anti-nociception.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Behavior, Animal; Benzazepines; Dopamine; Dopamine Antagonists; Dopamine beta-Hydroxylase; Dose-Response Relationship, Drug; Electrochemistry; Heroin; Male; Morphine; Neurons; Oxidopamine; Pain Measurement; Periaqueductal Gray; Phosphopyruvate Hydratase; Rats; Rats, Wistar; Reaction Time; Receptors, Dopamine D1; Salicylamides; Tyrosine 3-Monooxygenase

In the first experiment, responding was maintained for food under a fixed ratio (FR) 10 with a 6-min timeout reinforcement schedule. Eticlopride (0.1-1.0 mg/kg i.p.) dose-dependently decreased the number of food pellets obtained, whereas naltrexone (3-30 mg/kg i.p.) did not significantly alter responding. In the second experiment, intravenous self-administration of cocaine (vehicle, 125, 250 and 500 micrograms/infusion), heroin (vehicle, 5.4, 9 and 18 micrograms/infusion) and cocaine/heroin combinations were maintained under a FR10 reinforcement schedule. Cocaine/heroin combinations included the aforementioned cocaine doses combined with 5.4 micrograms/infusion heroin (CH5.4) or 18 micrograms/infusion heroin (CH18). Cocaine/heroin combinations dose-dependently decreased the number of infusions compared with cocaine alone. Eticlopride (0.03-0.3 mg/kg i.p.) decreased self-administration of 125 micrograms/infusion cocaine and increased self-administration of 500 micrograms/infusion cocaine. Self-administration of 250 micrograms/infusion cocaine was increased after 0.03 and 0.1 mg/kg and decreased after 0.3 mg/kg eticlopride. Eticlopride decreased heroin self-administration, an effect which may be attributable to its rate-decreasing effects. Eticlopride partially reversed the downward shift of the CH5.4 group but did not reverse the effect in the CH18 group. Naltrexone (1.0-10.0 mg/kg i.p.) decreased self-administration of 5.4 micrograms/infusion heroin and increased self-administration of 18 micrograms/infusion heroin. Self-administration of 9 micrograms/infusion heroin was increased by 1.0 mg/kg, not affected by 3.0 mg/kg and decreased by 10.0 mg/kg naltrexone. For the CH5.4 and CH18 groups, naltrexone dose-dependently shifted the dose-effect curves toward the cocaine dose-effect curve. Therefore, self-administration of cocaine/heroine combinations can be maintained in the rat and downward shifts in the cocaine dose-effect curve after combination with heroin are mediated through a naltrexone-sensitive mechanism.

Topics: Analysis of Variance; Animals; Cocaine; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Combinations; Eating; Heroin; Male; Naltrexone; Rats; Rats, Inbred F344; Receptors, Opioid; Salicylamides