Long-Term Antihyperalgesic and Opioid-Sparing Effects of 5-Day Ketamine and Morphine Infusion ("Burst Ketamine") in Diabetic Neuropathic Rats.

BACKGROUND: "Burst ketamine" (BK) is the long-term infusion of subanesthetic ketamine in combination with an opioid. It is used clinically with mixed success to provide long-term pain relief and improve opioid response in patients. BK has not been simulated preclinically, therefore, its effectiveness was investigated in an animal model of neuropathic pain--streptozotocin-induced diabetic neuropathy. METHODS: Diabetic neuropathic rats were randomized to receive a subcutaneous infusion of ketamine 20 mg/kg/day plus morphine 20 mg/kg/day (BK), either drug alone at the same dose, or sham treatment. Drugs were administered continuously over 5 days via osmotic minipump. Antihyperalgesic effects and antinociceptive responsiveness to morphine (0.625-10 mg/kg, i.p.) were assessed at 2, 4, 6, and 12 weeks post-treatment using paw withdrawal latency (PWL) from noxious heat (thermal hyperalgesia) and mechanical touch (tactile allodynia). RESULTS: Antihyperalgesic effects with significant increases in PWL from noxious heat occurred following BK and ketamine-only infusion, persisting 12 and 4 weeks, respectively. Opioid-sparing effects from noxious heat with increased sensitivity to morphine analgesia also occurred for 6 weeks after BK and 2 weeks after ketamine treatment; acute treatment with the maximum nonsedating dose of morphine (5 mg/kg) produced an antinociceptive effect in these two groups, but not in sham-treated rats. In morphine-only infusion rats, hyperalgesia and opioid insensitivity were both increased. CONCLUSIONS: This is the first preclinical study to use a model of neuropathic pain to demonstrate the utility of the BK procedure for delivering a long-lasting reduction in hyperalgesia and improved antinociceptive responsiveness to opioids.

Modulation of anxiety behavior in the elevated plus maze using peptidic oxytocin and vasopressin receptor ligands in the rat.

Oxytocin (OT) and arginine vasopressin (AVP), in their capacities as neuromodulators, are believed to play an important role in mood control, including regulation of the anxiety response. In the present study, the contributions of oxytocin and vasopressin receptor modulation to anxiety-like behaviors were examined in male Sprague-Dawley rats. The behavioral effects of the OT receptor agonist, carbetocin (intracerebroventricular, intravenous and intraperitoneal routes), the AVP receptor agonist desmopressin (intravenous route), and the OT/AVP(1A) receptor antagonist atosiban (intravenous route) were evaluated in the elevated plus maze. The benzodiazepine diazepam was included as a positive control. Central but not systemic administration of carbetocin produced pronounced anxiolytic-like behavioral changes comparable to those measured following systemic diazepam treatment. The anxiolytic efficacy of carbetocin was maintained following 10 days of once-daily treatment, contrasting with the effects of diazepam which were no longer distinguishable from saline treatment. Systemic administration of desmopressin produced anxiogenic-like effects whereas systemic atosiban produced anxiolytic-like effects. Co-administration of desmopressin with atosiban resulted in saline-like behavioral responses, implicating an AVP(1A) receptor mechanism in the anxiolytic and anxiogenic effects of these neuropeptides following systemic administration. A peripherally-mediated antidiuretic effect of desmopressin on water consumption was also demonstrated. These results highlight the potential therapeutic utility of AVP(1A) receptor blockade in the modulation of anxiety-related behaviors; AVP(1A) receptor blockade appears to be a more promising pharmacological target than does OT receptor activation following systemic drug administration.

Assessing the antidepressant-like effects of carbetocin, an oxytocin agonist, using a modification of the forced swimming test.

RATIONALE: The distribution of oxytocin receptors in limbic regions, as well as evidence that exogenous oxytocin modulates affect and fear processing, suggests that this neuropeptide may have a role to play in the treatment of mood disorders. OBJECTIVES: This study compared the effects of acute treatment with the oxytocin receptor agonist, carbetocin with the tricyclic antidepressant, imipramine, using male Sprague-Dawley rats. METHODS: Intracerebroventricular (i.c.v.; 1, 10, 100 microg/rat), intravenous (i.v.; 2.5, 5 mg/kg), and intraperitoneal (i.p.; 2, 6.4, 20 mg/kg) carbetocin and imipramine (1.8, 5.6, 10 mg/kg, i.p.) were examined in the modified forced swim and open field tests. The mechanism of action of carbetocin was investigated by co-administering it with the oxytocin antagonist, atosiban, either centrally (5 microg/rat, i.c.v.) or systemically (1 mg/kg, i.v.). RESULTS: Imipramine and carbetocin (all three routes of administration) both significantly reduced immobility and increased swimming and/or climbing behavior in the forced swim test. The systemic effects of carbetocin were blocked by central and systemic atosiban co-administration. Only amphetamine (2 mg/kg, i.p.), included as a false positive in order to distinguish whether antidepressant-like effects were due to psychomotor stimulation, increased locomotor activity in the open field test. CONCLUSIONS: Carbetocin produced antidepressant-like changes in behavior via activation of oxytocin receptors in the CNS. The similarities between imipramine and carbetocin in the forced swim test suggest that drugs which target the oxytocinergic system may aid both the understanding and pharmacological treatment of depressive illness.