Group II mGluR receptor agonists are effective in persistent and neuropathic pain models in rats.

The involvement of Group II metabotropic receptors in acute and persistent pain states was evaluated in several in vivo models of pain with selective and potent Group II metabotropic glutamate (mGlu) 2,3 agonists. LY354740, LY379268 and LY389795 attenuated late-phase paw-licking pain behavior in a dose-dependent manner in the formalin model of persistent pain. Effects occurred in the absence of overt neuromuscular deficits as measured by performance in the rotorod test for ataxia. The effects of LY354740 and LY379268 were also stereoselective. The order of potency of the agonists was LY389795>LY379268>LY354740. The attenuation of licking behavior by LY379268 (3 mg/kg) in the formalin model was reversed by a potent and selective mGlu2,3 receptor antagonist, LY341495 (1 mg/kg). In the L5/L6 spinal nerve ligation model of neuropathic pain in rats, LY379268 significantly reversed mechanical allodynia behavior in a dose-related manner. In contrast, LY379268 had no significant effects on the tail flick test or paw withdrawal test of acute thermal nociceptive function. These results support the involvement of Group II mGlu2,3 receptors in persistent pain mechanisms and suggest the potential utility of selective Group II mGlu agonists for the treatment of persistent pain.

Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats.

5-Hydroxytryptamine (serotonin) (5-HT) and norepinephrine (NE) are implicated in modulating descending inhibitory pain pathways in the central nervous system. Duloxetine is a selective and potent dual 5-HT and NE reuptake inhibitor (SNRI). The ability of duloxetine to antagonize 5-HT depletion in para-chloramphetamine-treated rats was comparable with that of paroxetine, a selective serotonin reuptake inhibitor (SSRI), whereas its ability to antagonize NE depletion in alpha-methyl-m-tyrosine-treated rats was similar to norepinephrine reuptake inhibitors (NRIs), thionisoxetine or desipramine. In this paradigm, duloxetine was also more potent than other SNRIs, including venlafaxine or milnacipran and amitriptyline. Low doses of the SSRI paroxetine or the NRI thionisoxetine alone did not have an effect on late phase paw-licking pain behavior in the formalin model of persistent pain; however, when combined, significantly attenuated this pain behavior. Duloxetine (3-15 mg/kg intraperitoneal) significantly attenuated late phase paw-licking behavior in a dose-dependent manner in the formalin model and was more potent than venlafaxine, milnacipran, and amitriptyline. These effects of duloxetine were evident at doses that did not cause neurologic deficits in the rotorod test. Duloxetine (5-30 mg/kg oral) was also more potent and efficacious than venlafaxine and milnacipran in reversing mechanical allodynia behavior in the L5/L6 spinal nerve ligation model of neuropathic pain. Duloxetine (3-30 mg/kg oral) was minimally efficacious in the tail-flick model of acute nociceptive pain. These data suggest that inhibition of both 5-HT and NE uptake may account for attenuation of persistent pain mechanisms. Thus, duloxetine may have utility in treatment of human persistent and neuropathic pain states.

Heart rate and motor-activating effects of orally self-administered ethanol in alcohol-preferring (P) rats.

BACKGROUND: Autonomic and behavioral arousals often accompany reinforcement. Additionally, contextual cues associated with alcohol consumption elicit increases in heart rate in alcoholics. This study examined changes in heart rate (HR) and motor activity before and during limited-access to ethanol, saccharin, or water in adult male alcohol-preferring (P) rats. METHODS: Adult male P rats were implanted with radiotelemetric transmitters to measure HR and motor activity. The experiment involved placing the animals in a test chamber for a 90-min pretest period, with water available. Thereafter, the animals were given a 90-min test session with access to one of three test solutions: water, 0.0125% saccharin, or 15% (v/v) ethanol (EtOH). After a week of habituation (water served as the test solution for all three groups), the animals were given their respective test solution for 3 weeks. RESULTS: Analyses of HR revealed that the saccharin and EtOH groups had significantly higher HR than the water group during the pretest period of the third test week. Both the saccharin and EtOH groups had significantly higher HR than the water group during the test period of all three test weeks. Analyses of motor activity revealed that the EtOH group displayed higher motor activity than the water and saccharin groups during the pretest period of the third test week. CONCLUSIONS: The data indicate that oral self-administration of EtOH enhances behavioral and autonomic activation, compared with saccharin or water, in adult male P rats and support previous observations that changes in HR can be used as an index of reinforcement. Additionally, it seems that the behavioral and autonomic activation elicited by EtOH self-administration can be conditioned to the environment in which EtOH was self-administered. These findings parallel reports on cued reactivity (behavioral and autonomic activation) in alcoholics exposed to alcohol-associated stimuli.