The selective norepinephrine (NE)

The blockade of serotonin (5-HT) and norepinephrine (NE) transporters in vitro and in vivo by the dual 5-HT

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 ␣-methyl-m-tyrosinetreated 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.

No abstract

The ability of the atypical antipsychotic drug candidate olanzapine to antagonize dopamine, serotonin, alpha-adrenergic and muscarinic receptors in vivo was assessed by various neurochemical measurements in rat brain. Olanzapine increased the concentrations of the dopamine metabolites DOPAC and HVA in striatum and nucleus accumbens. Olanzapine antagonized the pergolide-induced decrease of striatal DOPA concentrations in rats treated with gammabutyrolactone and NSD1015 and increased striatal 3-methoxytyramine concentrations in nomifensine-treated rats (but not after gammabutyrolactone administration), suggesting that olanzapine blocked terminal and somatodendritic autoreceptors on dopamine neurons. Inactivation of dopamine D1 and D2 receptors by EEDQ was antagonized by olanzapine. The ex vivo binding of the 5HT2 radioligand [3H]-ketanserin was inhibited by olanzapine treatment, as was quipazine-induced increases in MHPG-SO4, evidence suggesting that olanzapine antagonized 5HT2 receptors. At higher doses, olanzapine increased the concentrations of the norepinephrine metabolite, MHPG-SO4, probably by blocking alpha 1-adrenergic receptors. Olanzapine inhibited ex vivo binding of the muscarinic antagonist radioligand [3H]-pirenzepine and lowered concentrations of striatal, but not hippocampal, acetylcholine levels. The findings provide evidence that olanzapine antagonized dopamine, serotonin, alpha-adrenergic and muscarinic receptors in vivo, consistent with its high affinity for these receptor sites in vitro.