The mu/kappa agonist nalbuphine attenuates sensitization to the behavioral effects of cocaine

Abstract

Sensitization refers to an increase in sensitivity to a drug and is believed to play a role in the etiology of substance use disorders. The purpose of the present study was to evaluate the ability of the mixed mu/kappa agonist nalbuphine to modulate sensitization to the locomotor and positive reinforcing effects of cocaine. Rats were habituated to a locomotor activity chamber and treated with saline (1.0 ml/kg, ip), cocaine (10 mg/kg, ip), or cocaine + nalbuphine (10 mg/kg, ip) every day for 10 days. Following locomotor activity testing, rats were implanted with intravenous catheters and cocaine self-administration was examined on fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. Rats treated with cocaine exhibited a progressive increase in locomotor activity over the 10-day treatment period, and this effect was significantly reduced in rats treated with cocaine + nalbuphine. In self-administration tests, rats treated with cocaine exhibited significantly higher levels of responding at a threshold dose of cocaine (0.03 mg/kg/infusion) on both FR and PR schedules than rats treated with saline. This increase in responding at a threshold dose of cocaine was blocked completely in rats treated with cocaine + nalbuphine. These data suggest that nalbuphine attenuates the development of sensitization to the behavioral effects of cocaine.

The Brain on Drugs: From Reward to Addiction

“…Activation of KOR on DA terminals inhibits DA release in the NAc, which is implicated in the dysphoria that follows drug withdrawal (Tejeda et al, 2012). These findings have generated interest in KOR antagonists or partial agonists as medications to prevent relapse in addiction (Al-Hasani et al, 2013;Butelman et al, 2012;Grosshans et al, 2015;Schlosburg et al, 2013;Smith et al, 2013a). The effects of drugs on the opioid system in the human brain have been investigated with positron emission tomography (PET) using [ 11 C]carfentanil to assess MOR and their occupancy by enkephalins.…”

Synthesis and Pharmacological Evaluation of Aminothiazolomorphinans at the Mu and Kappa Opioid Receptors

“…10–13 Recent behavioral studies have suggested that mixed MOR and KOR activity may be useful for the treatment of addiction/dependence and cocaine abuse. 14–16 We have reported that treatment of rhesus monkeys with cyclorphan (an analog of levorphanol, Figure 1), which has mixed KOR and MOR activity, reduced cocaine self-administration and produced fewer side effects than κ-selective agonists. 17 Another analog, butorphan (Figure 1) in contrast to a partial effect with cyclorphan, exhibited full antinociception in the warm-water tail flick test in rats, 10b and was shown to be 40 times more potent in suppressing abstinence in morphine dependent monkeys.…”

Salvinorin A and Related Compounds as Therapeutic Drugs for Psychostimulant-Related Disorders

“…For instance, these compounds do not modify basal dopamine levels, a hallmark of the stimulants [21,25,30]. κ-Opioid receptor agonists attenuate stimulantinduced increases in locomotor activity in rats [21,29,46]. κ-Opioid agonists also decrease responding maintained by cocaine and reduce the reinstatement of abolished cocaine and amphetamine use in rats [24,28,31,32,38,46].…”

“…κ-Opioid receptor agonists attenuate stimulantinduced increases in locomotor activity in rats [21,29,46]. κ-Opioid agonists also decrease responding maintained by cocaine and reduce the reinstatement of abolished cocaine and amphetamine use in rats [24,28,31,32,38,46]. In mice, these compounds reduce the enhancement of dopamine release produced by non-neurotoxic doses of methamphetamine, and also inhibit the reduction of dopamine levels produced by neurotoxic doses of this stimulant [25].…”

“…As κ agonists control dopaminergic transmission, these compounds also interact with psychostimulants . Several cocaine-induced effects are inhibited by administration of κ agonists, including increases in dopamine levels [20,26,33,37,40,49], rewarding effects [24,26,32,33,[40][41][42]46], increases in locomotion and stereotypy [20,21,26,33,36,40,44,46,49], alterations in gene expression [26,33,36,43], and reinstatement of cocaine selfadministration [24,26,28,33,[38][39][40]50]. In monkeys, κ agonists reduce cocaine intake [19, 26, 33-35, 40, 48].…”