British journal of pharmacology
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Neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH) is a novel hypnotic and voltage-dependent blocker of T-type calcium channels. Here, we examine its potential analgesic effects and adjuvant anaesthetic properties using a post-surgical pain model in rodents. ⋯ Our study identifies 3β-OH as a novel analgesic for surgical procedures. 3β-OH can be used to reduce T-channel-dependent excitability of peripheral sensory neurons as an adjuvant for induction and maintenance of general anaesthesia while improving analgesia and lowering the amount of volatile anaesthetic needed for surgery.
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Considerable effort has recently been directed at developing multifunctional opioid drugs to minimize the unwanted side effects of opioid analgesics. We have developed a novel multifunctional opioid agonist, DN-9. Here, we studied the analgesic profiles and related side effects of peripheral DN-9 in various pain models. ⋯ DN-9 produces potent analgesia with minimal side effects, which strengthen the candidacy of peripherally acting opioids with multifunctional agonistic properties to enter human studies to alleviate the current highly problematic misuse of classic opioids on a large scale.
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The morbidity and mortality associated with recreational use of synthetic cannabinoid receptor agonists (SCRAs) may reflect strong activation of CB1 receptors and is a major health concern. The properties of SCRA at CB1 receptors are not well defined. Here we have developed an assay to determine acute CB1 receptor efficacy using receptor depletion with the irreversible CB1 receptor antagonist AM6544, with application of the Black and Leff operational model to calculate efficacy. ⋯ All SCRAs tested showed substantially higher efficacy at CB1 receptors than ∆9 -THC, which may contribute to the adverse effects seen with these drugs but not ∆9 -THC.
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The concept of opioid ligands biased towards the G protein pathway with minimal recruitment of β-arrestin-2 is a promising approach for the development of novel, efficient, and potentially nonaddictive opioid therapeutics. A recently discovered biased μ-opioid receptor agonist, PZM21, showed analgesic effects with reduced side effects. Here, we aimed to further investigate the behavioural and biochemical properties of PZM21. ⋯ PZM21 exhibited antinociceptive efficacy, without rewarding or reinforcing properties. However, its clinical application may be restricted, as it induces tolerance and withdrawal symptoms. Notably, its ability to diminish morphine reward implies that PZM21 may be useful in treatment of opioid use disorders.
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Opioids remain the most efficient medications against severe pain; they act on receptors that couple to heterotrimeric G-proteins in the Gαi/o family. Opioids exert many of their acute effects through modulating ion channels via Gβγ subunits. Many of their side effects are attributed to β-arrestin recruitment. Several biased agonists that do not recruit β-arrestins, but activate G-protein-dependent pathways, have recently been developed. While these compounds have been proposed to be full agonists of G-protein signalling in several high throughput pharmacological assays, their effects were not studied on ion channel targets. ⋯ TRV130, PZM21, and potentially herkinorin are partial agonists of μ receptors.