Mechanism of opioid-induced pruritus through TRP channel in peripheral nervous system

Abstract

Opioids, such as morphine, are commonly used as narcotic analgesics for clinical pain management, often leading to acute pruritus as a common side effect. While the mechanisms of opioid induced itch in central nervous system are better understood, the underlying mechanisms of peripheral opioid-induced itch remain insufficiently elucidated. In this study, I identified the receptors and transient receptor potential (TRP) channels present on peripheral sensory neurons responsible for eliciting opioid-induced scratching in mice. Intradermal morphine induces scratching peripherally, separate from its pain-relief effects. Naloxone Methiodide stops this scratching and halts calcium responses triggered by morphine in DRG cells. DAMGO, a Mu-opioid receptor (MOR) agonist, causes itching. Resiniferatoxin (RTX)-treated model almost reduces DAMGO-induced itching, while Loratadine has a slightly effect. DRG neurons activated by MOR show calcium influx and respond to TRPC4 activators. Blocking TRPC4 with ML204 inhibits MOR-induced calcium influx, and TRPC4 knock out mouse DRG does not show MOR-induced calcium influx. The calcium influx facilitated by TRPC4 was hindered by substances like pertussis toxin (PTX) which dissociates Gi proteins, the Gi protein inhibitor N-ethylmaleimide (NEM), and the adenyl cyclase (AC) activator Forskolin. This suggests that the pathway involved in this process is related to Gi/o rather than Gq/11. Indeed, modulation of TRPC4 showed a reduction in intradermal opioid-induced itch behavior. TRPC4KO mice scratched less when given peripheral DAMGO. Blocking TRPC4 in DRG cells using siRNA and ML204 also reduced scratching. Through immunohistochemistry, I confirmed TRPC4 presence in mouse skin nerve endings, with 76.19% of DRG cells showing both MOR and TRPC4. This suggests that opioids in the periphery trigger calcium entry via TRPC4, generating itch signals. These findings hint at new treatments for itchiness linked to opioid use, offering insights for acute and chronic pruritus therapies.