Kappa opioid receptor (KOR) signaling on peripheral sensory neurons in vitro and in vivo

Considerable interest has developed in understanding the regulation of peripheral opioid receptors to avoid central nervous system‐mediated side effects of opioid pharmacotherapy. However, little is known about peripherally restricted KOR‐mediated analgesic responses. Here we studied KOR agonist‐signaling responses in primary cultures of sensory neurons and in a rat model of thermal allodynia. The KOR agonist, U50488, did not inhibit PGE2‐stimulated adenylyl cyclase (AC) activity in vitro nor PGE2‐induced thermal allodynia in vivo unless cells/tissue were pretreated with the inflammatory mediator bradykinin (BK). In contrast, U50488 stimulated ERK activity without BK pretreatment, which suggests that not all KOR‐mediated responses require pre‐exposure to an inflammatory mediator. Interestingly, the duration of U50488‐induced anti‐allodynia was inversely related to dose, suggesting that the KOR system desensitizes or that KOR activation may initiate both pro‐ and anti‐nociceptive pathways. These results indicate that KOR signaling to AC and ERK is differentially regulated in peripheral sensory neurons. A better understanding of how KOR are regulated on peripheral sensory neurons may provide for improved approaches for the treatment of pain that are devoid of CNS adverse effects. Supported by DA026619.