Selective activation of peripheral κ opioid receptors (KORs) may overcome the dose-limiting adverse effects of conventional opioid analgesics. We recently developed a vicinal disulfide-stabilized class of peptides with subnanomolar potency at the KOR. The aim of this study was to assess the analgesic effects of one of these peptides, named conorphin-1, in comparison with the prototypical KOR-selective small molecule agonist U-50488, in several rodent pain models. Surprisingly, neither conorphin-1 nor U-50488 were analgesic when delivered peripherally by intraplantar injection at local concentrations expected to fully activate the KOR at cutaneous nerve endings. While U-50488 was analgesic when delivered at high local concentrations, this effect could not be reversed by coadministration with the selective KOR antagonist ML190 or the nonselective opioid antagonist naloxone. Instead, U-50488 likely mediated its peripheral analgesic effect through nonselective inhibition of voltage-gated sodium channels, including peripheral sensory neuron isoforms NaV1.8 and NaV1.7. Our study suggests that targeting the KOR in peripheral sensory nerve endings innervating the skin is not an alternative analgesic approach.

Analgesics are commonly used over-the-counter (OTC) medicines readily available for purchase, sometimes without advice of a health professional. However, analgesics can cause harm even when taken according to dosing recommendations. Young adults may be more vulnerable to harm if they perceive low risk with OTC analgesic use, or struggle to interpret dosing instructions. This study aimed to explore factors affecting how young adults use OTC analgesics and associated perceptions of safety. An online survey was distributed to school-leavers and university students (17 to 25 years), in South-East Queensland, Australia, in the period November–December 2019. Most of the 302 respondents (school-leavers n = 147, university students n = 155) did not use analgesics frequently. School-leavers deferred to parents for analgesic information, while university students preferred the internet. The majority of respondents appeared safety conscious and did not take outside indicated use or instructions. However, a small proportion reported taking analgesics for an inappropriate indication. The difference in preferred source of analgesic information may reflect experience with analgesic use, increasing autonomy or decreased parental influence. Whilst it is encouraging that the majority of young adults appeared safety conscious, greater insight is needed into factors influencing decision making on OTC use, e.g., medicines knowledge, and changes with increasing age.