Search

Ketamine has been shown to produce analgesia in various acute and chronic pain states; however, abuse liability concerns have limited its utility. The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) has been shown to produce antidepressant-like effects similar to ketamine without abuse liability concerns. (2R,6R)-HNK produces sustained analgesia in models of chronic pain, but has yet to be evaluated in models of acute pain. The present study evaluated the efficacy of acute (2R,6R)-HNK administration (one injection) in assays of pain-stimulated (52- and 56-degree hot plate test and acetic acid writhing) and pain-depressed behavior (locomotor activity and rearing) in male and female C57BL/6 mice. In assays of pain-stimulated behaviors, (2R,6R)-HNK (1–32 mg/kg) failed to produce antinociception in the 52- and 56-degree hot plate and acetic acid writhing assays. In assays of pain-depressed behaviors, 0.56% acetic acid produced a robust depression of locomotor activity and rearing that was not blocked by pretreatment of (2R,6R)-HNK (3.2–32 mg/kg). The positive controls morphine (hot plate test) and ketoprofen (acetic acid writhing, locomotor activity, and rearing) blocked pain-stimulated and pain-depressed behaviors. Finally, the effects of intermittent (2R,6R)-HNK administration were evaluated in 52-degree hot plate and pain-depressed locomotor activity and rearing. Intermittent administration of (2R,6R)-HNK also did not produce antinociceptive effects in the hot plate or pain-depressed locomotor activity assays. These results suggest that (2R,6R)-HNK is unlikely to have efficacy in treating acute pain; however, the efficacy of (2R,6R)-HNK in chronic pain states should continue to be evaluated. [ABSTRACT FROM AUTHOR]

Background: Intermittent access to ethanol drives persistent escalation of intake and rapid transition from moderate to compulsive‐like drinking. Intermittent ethanol drinking may facilitate escalation of intake in part by altering aversion‐sensitive neural substrates, such as the insular cortex (IC), thus driving greater approach toward stimuli previously treated as aversive. Methods: We conducted a series of experiments in rats to examine behavioral and neural responses associated with escalation of ethanol intake. First, taste reactivity analyses quantified the degree to which intermittent brief‐access ethanol exposure (BAEE) alters sensitivity to the aversive properties of ethanol. Next, we determined whether pharmacological IC inhibition facilitated ethanol escalation. Finally, given that the IC is primary gustatory cortex, we employed psychophysical paradigms to assess whether escalation of ethanol intake induced changes in ethanol taste. These paradigms measured changes in sensitivity to the intensity of ethanol taste and whether escalation in intake shifts the salient taste quality of ethanol by measuring the degree to which the taste of ethanol generalized to a sucrose‐like ("sweet") or quinine‐like ("bitter") percept. Results: We found a near‐complete loss of aversive oromotor responses in ethanol‐exposed relative to ethanol‐naïve rats. Additionally, we observed significantly lower expression of ethanol‐induced c‐Fos expression in the posterior IC in exposed rats relative to naïve rats. Inhibition of the IC resulted in a modest, but statistically reliable increase in the acceptance of higher ethanol concentrations in naïve rats. Finally, we found no evidence of changes in the psychophysical assessment of the taste of ethanol in exposed, relative to naïve, rats. Conclusions: Our results demonstrate that neural activity within the IC adapts following repeated presentations of ethanol in a manner that correlates with reduced sensitivity to the aversive hedonic properties of ethanol. These data help to establish that alterations in IC activity may be driving exposure‐induced escalations in ethanol intake. [ABSTRACT FROM AUTHOR]