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In preclinical research on pain and analgesia, noxious stimuli can stimulate expression of some behaviors (e.g. withdrawal reflexes) and depress others (e.g. feeding, locomotion, and positively reinforced operant responding). Tolerance to morphine antinociception is a robust and reliable phenomenon in preclinical assays of pain-stimulated behavior, but development of morphine tolerance in assays of pain-depressed behavior has not been studied. This study compared morphine antinociceptive tolerance in parallel assays of pain-stimulated and pain-depressed behavior in male Sprague–Dawley rats. Intraperitoneal injection of dilute lactic acid served as a noxious stimulus to stimulate a stretching response in one group of rats and to depress operant responding for electrical brain stimulation (intracranial self-stimulation; ICSS) in another group of rats. Antinociception produced by morphine (1.0 mg/kg) was determined after a regimen of chronic treatment with either saline or morphine in separate subgroups of rats in each procedure. In rats receiving chronic saline, acid alone stimulated a stretching response and depressed ICSS, and both acid effects were blocked by 1.0 mg/kg morphine. Rats receiving chronic morphine displayed hyperalgesic responses to the acid noxious stimulus in both procedures. Complete tolerance developed to morphine antinociception in the assay of acid-stimulated stretching, but morphine retained full antinociceptive effectiveness in the assay of acid-depressed ICSS. These results suggest that morphine antinociception in an assay of pain-depressed behavior is relatively resistant to tolerance. More broadly, these results suggest that antinociceptive tolerance can develop at different rates or to different degrees for different measures of antinociception. [ABSTRACT FROM AUTHOR]

There is considerable evidence that mu opioid receptors are involved in the regulation of anterior pituitary function. For example, in nonhuman primates and humans, mu agonists generally increase prolactin (PRL) levels. In contrast, mu antagonists decrease or have no effect on PRL levels. The goal of this study was to assess the potential utility of cumulative-dosing procedures to evaluate the endocrine effects of mu opioid receptor ligands. The effects of single and multiple, cumulative doses of the mu agonist heroin and the mu-selective antagonist quadazocine on PRL levels were investigated in four male rhesus monkeys. Cumulative dose-response curves were determined by infusing increasing drug doses at 60 min intervals over 290 min. Blood samples for PRL analysis were collected at 25 and 50 min after each cumulative infusion. Samples were collected at similar time points following single drug dose administration. Heroin (0.01–0.32 mg/kg, IV) administration dose-dependently increased PRL levels. Maximum levels of heroin-induced PRL levels were equivalent after single and cumulative doses. Quadazocine alone (0.032–1.0 mg/kg, IM) did not alter PRL levels significantly. However, quadazocine (0.1 mg/kg, IM) antagonized heroin-stimulated increases in PRL levels and produced a significant rightward shift in the heroin dose-effect curve. These data suggest that a cumulative-dosing procedure similar to that used in behavioral pharmacology may be useful to study the endocrine pharmacology of mu opioids in rhesus monkeys. [Copyright &y& Elsevier]

Neuropeptide S (NPS) is a neurotransmitter that activates the NPS receptor to modulate biological functions including anxiety-like behaviors, feeding, and drug reinforcement. RTI-118 is a novel NPS receptor antagonist that decreased cocaine self-administration in rats at doses that had little or no effect on food-maintained responding. To build on these previous findings, this study examined effects of RTI-118 on cocaine-induced facilitation of intracranial self-stimulation (ICSS) in rats. To provide a context for data interpretation, effects of RTI-118 were compared to effects of the kappa opioid receptor agonist U69,593, because the kappa opioid receptor is another peptide neurotransmitter receptor reported to modulate abuse-related cocaine effects. RTI-118 effects were also examined on ICSS facilitation produced by methylenedioxypyrovalerone (MDPV), a novel designer drug of abuse with some cocaine-like effects. Male Sprague–Dawley rats ( n =12) with electrodes targeting the medial forebrain bundle responded under a fixed-ratio 1 schedule for range of brain stimulation frequencies. Under control conditions, brain stimulation maintained a frequency-dependent increase in ICSS rates. Cocaine (1.0–10 mg/kg) and MDPV (3.2 mg/kg) facilitated ICSS. RTI-118 (3.2–32 mg/kg) alone produced little effect on ICSS but dose dependently blocked cocaine-induced ICSS facilitation. U69,593 (0.25–0.5 mg/kg) also attenuated cocaine effects, but blockade of cocaine effects was incomplete even at a U69,593 dose that alone depressed ICSS. RTI-118 (32 mg/kg) failed to block MDPV-induced ICSS facilitation. These results support further consideration of NPS receptor antagonists as candidate treatments for cocaine abuse and provide evidence for differential effects of a candidate treatment on abuse-related effects of cocaine and MDPV. [ABSTRACT FROM AUTHOR]