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.

Activation of a NO-cyclic GMP system by NO donors potentiates beta-endorphin-induced antinociception in the mouse.

Nitric oxide (NO) donors such as sodium nitroprusside (SNP, 0.01-1 micrograms) or 3-morpholino-sydnonimine (SIN-1, 0.1-10 micrograms) administered intracerebroventricularly (i.c.v) produced a dose-dependent potentiation of beta-endorphin-induced antinociception assessed by the tail-flick test in ICR mice. The same i.c.v. treatment with SNP or SIN-1 did not affect the antinociception induced by mu-, delta-, or kappa-opioid receptor agonists. The goal of the present study was to determine if the potentiation of the beta-endorphin-induced antinociception by NO donors is mediated by the activation of NO-cGMP system. Co-administration of hemoglobin (30-120 micrograms) or methylene blue (1.25-5 micrograms), but not N omega-nitro-L-arginine (1-5 micrograms) given i.c.v. dose-dependently attenuated the potentiating effects of SNP or SIN-1 on beta-endorphin-induced antinociception. However, the same i.c.v. treatments of mice with hemoglobin, methylene blue or N omega-nitro-L-arginine did not directly affect the i.c.v. administered beta-endorphin-induced antinociception. On the other hand, the treatment of mice with a combination of NO donor (SNP, 0.1 micrograms or SIN-1, 1 microgram) and zaprinast (a cGMP phosphodiesterase inhibitor, 1 microgram) further potentiated beta-endorphin-induced antinociception. These results indicate that the potentiating effect of SNP or SIN-1 on beta-endorphin-induced antinociception is mediated by the increased production of NO-cyclic GMP in the brain. However, the NO-cGMP system is not directly involved in the beta-endorphin-induced antinociception.