Differential sensitivity of opioid-induced feeding to naloxone and naloxonazine

Abstract

The high-affinity mu-1 opioid binding site has been implicated in some opioid responses (e.g., supraspinal analgesia) but not others (e.g., respiratory depression) by comparing the actions of naloxone, a short-acting, non-selective antagonist, and naloxonazine, an irreversible and selective mu-1 antagonist. The mu-1 site has been implicated in the opioid component modulating free feeding and deprivation-induced feeding, but not glucoprivic feeding. The present study compared naloxone and naloxonazine antagonism of hyperphagia induced by morphine, ethylketocyclazocine (EKC), dynorphin and d-ala2,d-leu5-enkephalin (DADL) in rats. Morphine produced a dose-dependent (0.01-5 mg/kg) hyperphagia in mildly food-deprived rats that was blocked by naloxone (0.01-10 mg/kg). Naloxonazine (10 mg/kg) shifted the morphine hyperphagia dose-response curve to the right. These effects could not be fully accounted for by the intrinsic hypophagic properties of these antagonists. EKC produced a dose-dependent (0.5-5 mg/kg) hyperphagia which was blocked by naloxone (10 mg/kg) only at low effective EKC doses. Naloxonazine (10 mg/kg) failed to affect EKC hyperphagia. Naloxone, but not naloxonazine also blocked dynorphin and DADL hyperphagia. These results indicate that feeding induced by opiate and opioid agonists are differentially mediated by the mu-1 and other opioid binding sites; these data contrast with the modulation by the mu-1 site of the supraspinal analgesia induced by each of these agonists.

Pain-suppressed consumption of highly palatable liquid in rats

“…In other studies, morphine did not reverse acid-suppressed consumption of a highly palatable liquid (Miller et al ., 2011, 2012), or CFA-suppressed burrowing (Gould et al ., 2016; but see Craft, 2023), but did significantly increase pain-suppressed locomotor activity (Stevenson et al ., 2009; Matson et al ., 2010; Miller et al ., 2011, 2012), wheel-running (Kandasamy et al ., 2017), and nesting (Negus et al ., 2015), either without changing or decreasing these behaviors in controls. Given that acutely administered morphine has been shown to increase food consumption per se in rats (Mann et al ., 1988; Gulati et al ., 1991), hyperphagia cannot be ruled out as an alternative explanation for morphine’s effects in the present study.…”

A naloxonazine sensitive (μ1 receptor) mechanism in the parabrachial nucleus modulates eating

“…For example, intravenous injection of Nlxz 24h prior to free-feeding or intraventricular infusion of this drug, significantly reduced food consumption (Ling et al, 1986; Mann et al, 1988a; Ragnauth et al, 2000; Simone et al, 1985). Chronic blockade of µ 1 receptors by Nlxz produced a rightward shift in the morphine hyperphagia dose-response curve reducing food intake below vehicle values (Mann et al, 1988b).…”

“…Additionally, intravenous (i.v.) administration of Nlxz, by itself, reduced food intake in adult male rats (Ling et al, 1986; Mann et al, 1988a; Mann et al, 1988b; Simone et al, 1985). …”

μ‐Opioid Receptor Ligands Lack Receptor Subtype Selectivity in the Aequorin Luminescence‐based Calcium Assay

“…μ‐Opioid receptors were divided into μ 1 ‐ and μ 2 ‐subtypes based on their sensitivity to the μ‐opioid receptor antagonist naloxonazine, which irreversibly binds to the μ 1 ‐opioid receptors (3,4) and inhibits the supraspinal antinociception as assayed with the formalin, hot plate, tail‐pressure, and tail‐flick tests (5–7). The μ 1 ‐opioid receptors might also be implicated in the modulation of acetylcholine release and some aspects of feeding and withdrawal signs (8–11). The μ 2 ‐opioid receptors might mediate naloxonazine‐insensitive spinal antinociception, respiratory depression, inhibition of gastrointestinal transit, and withdrawal signs (11–13).…”