Neuropharmacology
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Oxidized lipids play an important role in pain processing by modulation of the activity of sensory neurons. However, the role of many signalling lipids that do not belong to the classical group of eicosanoids, especially of oxidized omega-3 lipids in pain processing is unclear. Here we investigated the role of the endogenously produced omega-3 lipids 17,18-EEQ and 19,20-EDP in modulating the activity of sensory neurons. ⋯ These findings identify 17,18-EEQ as first omega-3-derived lipid mediator that acts via the IP receptor and sensitizes the TRPV1 channel in sensory neurons. Moreover, the results give a mechanistic explanation for the antinociceptive effects of venlafaxine, which are still not well understood. Like telmisartan, venlafaxine may reduce neuronal activity by blocking CYP2J2 and 17,18-EEQ synthesis and by inhibiting the IP receptor-PKA-TRPV1 axis in sensory neurons.
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Binding and signaling kinetics have previously proven important in validation of biased agonism at GPCRs. Here we provide a comprehensive kinetic pharmacological comparison of clinically relevant μ-opioid receptor agonists, including the novel biased agonist oliceridine (TRV130) which is in clinical trial for pain management. We demonstrate that the bias profile observed for the selected agonists is not time-dependent and that agonists with dramatic differences in their binding kinetic properties can display the same degree of bias. ⋯ GRK2 and GRK5 overexpression greatly increased μ-opioid receptor internalization induced by morphine, but only had modest effects on buprenorphine and oliceridine-induced internalization. Overall, our data reveal that the clinically available drug buprenorphine displays a similar pharmacological bias profile in vitro compared to the clinical candidate drug oliceridine and that this bias is independent of binding kinetics suggesting a mechanism driven by receptor-conformations. This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'.