Morphine Side Effects in β-Arrestin 2 Knockout Mice

TLDR

Morphine is a potent analgesic but causes side effects such as constipation and respiratory suppression, and pharmacological attempts to separate benefits from harms have largely failed, while β‑arrestin 2 knockout mice show markedly altered morphine responses. The study investigates whether disrupting μ‑opioid receptor regulation via β‑arrestin 2 knockout can separate morphine’s analgesic benefits from its side effects. β‑arrestin 2 knockout mice exhibit stronger, longer‑lasting analgesia with minimal tolerance, and markedly reduced respiratory suppression and acute constipation compared to wild‑type mice.

Abstract

Morphine is a potent analgesic, yet, like most opioid narcotics, it exerts unwanted side effects such as constipation and respiratory suppression, thereby limiting its clinical utility. Pharmacological approaches taken to preserve the analgesic properties, while eliminating the unwanted side effects, have met with very limited success. Here, we provide evidence that altering μ opioid receptor regulation may provide a novel approach to discriminate morphine9s beneficial and deleterious effects in vivo. We have previously reported that mice lacking the G protein-coupled receptor regulatory protein, β-arrestin 2, display profoundly altered morphine responses. β-Arrestin 2 knockout mice have enhanced and prolonged morphine analgesia with very little morphine tolerance. In this report, we examine whether the side effects of morphine treatment are also augmented in this animal model. Surprisingly, the genetic disruption of opioid receptor regulation, while enhancing and prolonging analgesia, dramatically attenuates the respiratory suppression and acute constipation caused by morphine.