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.
"a primary analgesic effect (Max et al., 1992; Fishbain et al., 2000; Finnerup et al., 2005; Atkinson et al., 2007; Verdu et al., 2008; Arnold et al., 2012). SSRIs can augment the activity of a selective NE reuptake inhibitor (Fishbain et al., 2000; Iyengar et al., 2004; Finnerup et al., 2005; Hall et al., 2011), and we hypothesize that an inhibitor with modest selectivity for NET instead would offer the potential for robust pain relief while minimizing any putative serotonergic side effects such as nausea, somnolence, fatigue, and sexual dysfunction (Papakostas, 2008). "
"However, the influence of intraplantar administration on mechanical allodynia was important to address. Similarly, in an inflammatory model of pain, amitriptyline treatment reduced pain behavior in the mouse in the late phase after formalin administration , and this action was stronger than that of venlafaxine. The effect of doxepin was similar to that of amitriptyline in our experiments. "
[Show abstract][Hide abstract] ABSTRACT: Background:
The therapy of neuropathic pain may include the use of co-analgesics, such as antidepressants, however, their desired analgesic effect is associated with significant side effects. An alternative approach to this is their local administration which has been proposed, but there is little data regarding their local co-administration with morphine and the nature of the interaction between morphine and either doxepin or venlafaxine, two antidepressant drugs that have been recently used in neuropathic pain therapies.
This study was performed on rats after chronic constriction injury (CCI) to the sciatic nerve. The von Frey and Hargreaves' tests were used to assess mechanical allodynia and thermal hyperalgesia, respectively, after intraplantar (ipl) or subcutaneous (sc) administration of amitriptyline, doxepin, or venlafaxine, or their ipl co-administration with morphine on day 12-16 after injury.
The ipl administration of amitriptyline (3, 15 mg), doxepin (1, 5, 10, 15 mg), or venlafaxine (2, 7 mg) was effective in antagonizing CCI-induced allodynia. Their sc injection at a site distal to the injured side, did not induce alterations in pain thresholds, which supports the local mode of action. Of the three antidepressants used in this study, only ipl co-administration of amitriptyline with morphine significantly enhanced its effect in contrast to doxepin and venlafaxine, both of which weakened the analgesic effect of morphine.
In summary, the results suggest that when amitriptyline (but not doxepin or venlafaxine) is locally co-administered with morphine the effectiveness under neuropathic pain is enhanced, although additional studies are necessary to explain differential mechanisms of interaction of antidepressant drugs with morphine after local administration.
"The doses of amitriptyline and carbamazepine were taken from studies that demonstrated efficacy in peripheral neuropathic pain models (De Vry et al. 2004c; Bomholt et al. 2005). Furthermore, the dose of amitriptyline used in this study has been shown to significantly increase rat brain concentrations of norepinephrine and serotonin (Iyengar et al. 2004). The dose of gabapentin was also selected based on a previous study – in this study, the 50% antinociceptive dose (A 50 ) was used in order to visualize either an improvement or decrement of efficacy over time (Hama and Sagen 2007b). "
[Show abstract][Hide abstract] ABSTRACT: A lack of efficacy of some analgesic drugs has been previously described in rats with neuropathic spinal cord injury (SCI) pain. It has been suggested that repeated dosing in these animals over time may eventually lead to efficacy. However, it is also possible that efficacy may diminish over time with repeated dosing. This study evaluated the efficacy of various drugs upon repeated dosing over time in a rat model of SCI pain. Four weeks following an acute spinal cord compression at the mid-thoracic level, rats developed decreased hind paw withdrawal threshold, suggestive of below level neuropathic hypersensitivity. Either cannabinoid (CB) receptor agonist CP 55,940, the anticonvulsant carbamazepine or gabapentin, the antidepressant amitriptyline or vehicle was administered over a period of 7 days. Neither carbamazepine nor amitriptyline demonstrated efficacy either after a single or repeated dosing. Beginning with a 50% efficacious dose of gabapentin, the effect of gabapentin in SCI rats neither increased nor decreased over the treatment period. The antinociceptive effect of CP 55,940 was maintained for the entire treatment period, which was mediated by CB1 but not CB2 receptors. The current data suggest that sustained antinociception can be obtained with some drugs in rats with neuropathic SCI pain. Furthermore, the current data do not substantiate the notion that repeated treatment with initially ineffective drugs will eventually lead to efficacy; treatments that are not acutely effective are unlikely to demonstrate clinical efficacy.
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