Effects of monoamine reuptake inhibitors in assays of acute pain-stimulated and pain-depressed behavior in rats.

UNLABELLED: Pain is associated with stimulation of some behaviors (eg, withdrawal reflexes) but depression of many other behaviors (eg, feeding, locomotion, positively reinforced operant behavior). Drugs that block reuptake of serotonin, norepinephrine, and/or dopamine are widely used to treat depression, and they have also emerged as useful drugs for treatment of pain. This study compared effects of selective and mixed-action inhibitors of serotonin, norepinephrine, and/or dopamine reuptake in assays of acute pain-stimulated and pain-depressed behavior. Intraperitoneal injection of dilute acid served as a noxious stimulus to stimulate a writhing response or depress intracranial self-stimulation (ICSS) in Sprague Dawley rats. Selective reuptake inhibitors of serotonin (citalopram, clomipramine) and norepinephrine (nisoxetine, nortriptyline) and a mixed-action reuptake inhibitor of serotonin and norepinephrine (milnacipran) blocked acid-stimulated writhing but failed to block acid-induced depression of ICSS. Selective dopamine reuptake inhibitors (RTI-113 [3ß-(4-chlorophenyl)tropane-2ß-carboxylic acid phenyl ester hydrochloride], bupropion) and a triple reuptake inhibitor of dopamine, serotonin, and norepinephrine (RTI-112 [3ß-(3-methyl-4-chlorophenyl)tropane-2ß-carboxylic acid methyl ester hydrochloride]) blocked both acid-stimulated writhing and acid-induced depression of ICSS, although these drugs also produced an abuse-related facilitation of ICSS in the absence of the noxious stimulus. These results support further consideration of dopamine reuptake inhibitors as candidate analgesics, although abuse liability remains a concern. PERSPECTIVE: Monoamine reuptake inhibitors are used to treat depression and some forms of pain. This study examined effects of monoamine reuptake inhibitors in a preclinical assay of pain-related behavioral depression. The results support further consideration of dopamine reuptake inhibitors as candidate analgesics under selected circumstances, although abuse liability remains a concern.

Effects of the δ opioid receptor agonist SNC80 on pain-related depression of intracranial self-stimulation (ICSS) in rats.

UNLABELLED: The delta opioid receptor agonist SNC80 produces both antinociceptive and antidepressant effects in rodents. This profile suggests that SNC80 may also reverse prodepressant effects of pain. Accordingly, this study compared SNC80 effects in complementary assays of pain-stimulated and pain-depressed behavior in rats. Intraperitoneal injection of dilute acid served as an acute noxious visceral stimulus in rats to stimulate abdominal stretching (a pain-stimulated behavior) or depress intracranial self-stimulation of the medial forebrain bundle (ICSS; a pain-depressed behavior). When administered once per week to minimize acute tolerance, SNC80 (1-10 mg/kg IP) decreased acid-stimulated stretching but had little effect on acid-induced depression of ICSS. More frequent SNC80 administration produced tolerance to SNC80 effects on acid-stimulated stretching, but unmasked antinociception in the assay of acid-depressed ICSS. SNC80 did not facilitate ICSS in the absence of pain, and effects of SNC80 were not duplicated by ARM390, a reputed delta agonist congener of SNC80 that does not internalize delta receptors. These findings support continued consideration of delta agonists as candidate analgesics to treat prodepressant effects of pain and illustrate the potential for diametrically opposite effects of drug treatments on preclinical measures of pain-stimulated and pain-depressed behavior. PERSPECTIVE: The delta opioid agonist SNC80 blocked pain-related depression of intracranial self-stimulation in rats, suggesting that delta agonists may be useful to treat prodepressant effects of pain. Repeated SNC80 produced tolerance to SNC80 antinociception in a conventional assay of pain-stimulated behavior but unmasked SNC80 antinociception in an assay of pain-depressed behavior.

Effects of kappa opioids in an assay of pain-depressed intracranial self-stimulation in rats.

RATIONALE: Selective, centrally acting kappa opioid agonists produce antinociception in a wide range of preclinical assays, but these compounds perform poorly as analgesics in humans. This discrepancy may be related to the behavioral depressant effects of kappa agonists. Kappa antagonists do not typically produce antinociception, but they produce antidepressant-like effects in some preclinical assays. OBJECTIVE: The objective of this study was to test the hypothesis that the kappa agonist U69,593 and the kappa antagonist norbinaltorphimine would produce pronociceptive and antinociceptive effects, respectively, in an assay of pain-depressed behavior. METHODS: Effects of U69,593 (0.056-0.56 mg/kg), norbinaltorphimine (10-32 mg/kg), and morphine (3.2 mg/kg) were evaluated on the stimulation of a stretching response and the depression of intracranial self-stimulation (ICSS) of the medial forebrain bundle produced in rats by a common noxious stimulus (intraperitoneal administration of dilute lactic acid). RESULTS: U69,593 produced a dose-dependent blockade of acid-stimulated stretching but only exacerbated acid-induced depression of ICSS. Thus, U69,593 produced antinociception in the assay of pain-stimulated behavior but pronociceptive effects in the assay of pain-depressed behavior. Norbinaltorphimine did not alter acid-stimulated stretching or acid-induced depression of ICSS. The mu opioid agonist morphine blocked both acid-stimulated stretching and acid-induced depression of ICSS. CONCLUSIONS: These results support the hypothesis that prodepressant effects of kappa agonists may limit their clinical utility as analgesics. These results do not support the use of kappa antagonists to treat depressant effects of pain. These findings illustrate the potential value of using complementary assays of pain-stimulated and pain-depressed behaviors for preclinical evaluation of candidate analgesics.

The CB1 antagonist rimonabant (SR141716) blocks cue-induced reinstatement of cocaine seeking and other context and extinction phenomena predictive of relapse.

Cannabinoid CB1 antagonists decrease self-administration of palatable food and several abused drugs in animals and modulate extinction of conditioned fear responses. Less is known, however, about whether and how CB1 antagonists might modulate the extinction of appetitive behavior. Therefore, this study examined the effects of the CB1 receptor antagonist rimonabant (SR141716) during extinction of responding maintained either by cocaine or by palatable foods (corn oil or Ensure), as well as responding elicited by stimulus cues that had been paired with the presentation of cocaine (i.e., cue-induced reinstatement) or a prime (presentation of cocaine or food). The effect of rimonabant on high rate responding in water-deprived mice trained to self-administer water was also examined. In mice self-administering cocaine, rimonabant attenuated cue-induced reinstatement of cocaine self-administration, the initial burst of responding during cocaine extinction and responding during spontaneous recovery. In mice self-administering corn oil, rimonabant decreased responding during extinction and also attenuated responding that had been reinstated by a priming presentation of corn oil. Moreover, mice treated with rimonabant required fewer daily sessions to reach criterion for extinction of cocaine-maintained responding than vehicle treated mice. Also, rimonabant had no effect on the rate of operant responding in mice trained to respond for water under an FR5 schedule of reinforcement. Taken together, these data suggest that in addition to attenuating the primary reinforcing effects of both palatable foods and drugs of abuse, CB1 receptor antagonism can attenuate context and cue reactivity during extinction learning and potentially enhance extinction learning in this way.