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  • Rickie Black posted an update 1 week, 4 days ago

    To our knowledge, these results represent the first quantitative demonstration that the balance between NET and SERT inhibition for a parenterally administrated monoamine reuptake inhibitor can influence the synergistic interaction with morphine in the rat formalin model. Our findings are consistent with numerous other studies that have reported synergy and/or additivity between morphine and agents that modulate 5-HT or NE pathways. Preclinically, in addition to the rat formalin model, synergistic interactions between monoamine reuptake inhibitors and morphine have also been observed in mouse tail-flick, rat thermal paw withdrawal and in preclinical pain models of postoperative pain. Recently, Schroder et. al. demonstrated a synergistic interaction between NET inhibition and m-receptor agonism in the low-intensity tail-flick and spinal nerve ligation rat models based on isobolographic analysis of estimated receptor/transporter occupancy for tapentadol. The predicted antinociceptive synergy with the dual mechanism tapentadol contrasts with our – conclusion that modest SERT engagement is required for antinociceptive synergy with morphine. The conflicting results could reflect different occupancy requirements in the rat formalin model compared with other models. It is also possible that the isobolographic analysis based on occupancy estimates calculated from tapentadol’s brain concentration could yield a different interpretation than one based on direct ex vivo occupancy measurements from rats monitored for nociceptive behavior, as in our current study. In clinical settings, desipramine, a TCA that inhibits NET preferentially over SERT, enhances morphine analgesia in post-operative dental pain patients. However, the clinical reports that duloxetine can reduce morphine consumption in both acute and chronic pain populations appear to be at odds with our preclinical finding of a lack of synergy between duloxetine and morphine and are worthy of further discussion. Possible discrepancies between the clinical and preclinical observations with duloxetine include dose – occupancy estimates and the technical limitations of each setting. As reported by positron emission tomography, at the therapeutic dose of 60 mg duloxetine achieves near-maximal occupancy of SERT, comparable to that observed in our current study. While the absolute level of NET occupancy achieved at therapeutic doses of duloxetine has not been reported, duloxetine likely engages NET at the clinical exposures. The difference between the clinical and the current preclinical findings with duloxetine may reflect different transporter occupancy requirements and/or differences in intrinsic NE and/or 5-HT tone in the preclinical model versus clinical pain states. An even simpler explanation of the potential discrepancy is that it is difficult to discriminate between additive and synergistic interactions in the clinical setting. As such, it is conceivable that the duloxetine clinical data represent simple additive effects of two analgesics with distinct mechanisms of action. Similarly, in the rat formalin model higher doses of duloxetine, which were antinociceptive in the absence of morphine, exhibited additivity with morphine. The neural substrates and MDV3100 corresponding mechanisms underlying a synergistic interaction between monoamines and opioids remain largely unknown. It has been shown that when a noxious stimulus is presented alone, activation of the endogenous pain modulatory pathway leads to a bilateral increase in the concentrations of both NE and 5-HT in the dorsal horn of the spinal cord. Coadministration of systemic morphine, in the presence of noxious stimulation, further increases the neuronal activity of brainstem noradrenergic, but not serotonergic, neurons. Electrophysiological or regional shRNA interference combined with behavioral techniques have demonstrated that activation of descending 5-HT containing neurons from the rostral ventromedial medulla is neither necessary, nor sufficient, for m-opioid receptor agonist-induced analgesia. Furthermore, interactions between a2-adrenoceptors and m-opioid receptors at the spinal level have also been reported. In the clinical arena, intrathecal clonidine is widely used in combination with morphine to afford equivalent pain-relief post-operatively, but with reduced morphine consumption.