Previously, we reported that oxycodone is a putative kappa-opioid agonist based on studies where intracerebroventricular (i.c.v.) pre-treatment of rats with the kappa-selective opioid antagonist, nor-binaltorphimine (nor-BNI), abolished i.c.v. oxycodone but not morphine antinociception, whereas pretreatment with i.c.v. naloxonazine (mu-selective antagonist) produced the opposite effects. In the present study, we used behavioural experiments in rat models of mechanical and biochemical nerve injury together with radioligand binding to further examine the pharmacology of oxycodone. Following chronic constriction injury (CCI) of the sciatic nerve in rats, the antinociceptive effects of intrathecal (i.t.) oxycodone, but not i.t. morphine, were abolished by nor-BNI. Marked differences were found in the antinociceptive properties of oxycodone and morphine in streptozotocin (STZ)-diabetic rats. While the antinociceptive efficacy of morphine was abolished at 12 and 24 weeks post-STZ administration, the antinociceptive efficacy of s.c. oxycodone was maintained over 24 weeks, albeit with an approximately 3- to 4-fold decrease in potency. In rat brain membranes irreversibly depleted of mu- and delta-opioid binding sites, oxycodone displaced [(3)H]bremazocine (kappa(2)-selective in depleted membranes) binding with relatively high affinity whereas the selective mu- and delta-opioid ligands, CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2)) and DPDPE ([D-Pen(2,5)]-enkephalin), respectively, did not. In depleted brain membranes, the kappa(2b)-ligand, leu-enkephalin, prevented oxycodone's displacement of high-affinity [(3)H]bremazocine binding, suggesting the notion that oxycodone is a kappa(2b)-opioid ligand. Collectively, the present findings provide further support for the notion that oxycodone and morphine produce antinociception through distinctly different opioid receptor populations. Oxycodone appears to act as a kappa(2b)-opioid agonist with a relatively low affinity for mu-opioid receptors.

The small molecule AT₂R antagonist, EMA401, is in clinical development as a novel analgesic for the relief of neuropathic pain.

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Over US$60 trillion is predicted to be spent on new infrastructure globally by 2040. Is it possible to meet UN Sustainable Development Goal (SDG) 9 (develop infrastructure networks) without sacrificing goals 14 and 15 (ending biodiversity loss)? We explore the potential role of ''no net loss'' (NNL) policies in reconciling these SDGs. We assess country-level overlaps between planned infrastructure expansion, infrastructure-threatened biodiversity, and national biodiversity compensation policies and find that around half of predicted infrastructure and infrastructure-threatened biodiversity falls within countries with some form of mandatory compensation policy. However, these policies currently have shortcomings, are unlikely to achieve NNL in biodiversity, and could risk doing more harm than good. We summarize policy transformations required for NNL policies to mitigate all infrastructure impacts on biodiversity. To achieve SDGs 9 alongside 14 and 15, capitalizing on the global coverage of mandatory compensation policies and rapidly transforming them into robust NNL policies (emphasizing impact avoidance) should be an urgent priority.

Loss of habitats or ecosystems arising from development projects (e.g., infrastructure, resource extraction, urban expansion) are frequently addressed through biodiversity offsetting. As currently implemented, offsetting typically requires an outcome of "no net loss" of biodiversity, but only relative to a baseline trajectory of biodiversity decline. This type of "relative" no net loss entrenches ongoing biodiversity loss, and is misaligned with biodiversity targets that require "absolute" no net loss or "net gain." Here, we review the limitations of biodiversity offsetting, and in response, This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.