Discerning the mechanisms by which TRPM3 inhibition by GΒΓ contributes to central- and peripheral-opioid-induced pruritus

Active Project Grant Awarded Last action

Award ID
F30NS141489
Recipient
Awarding agency
Obligated
$34,818

Award facts

Completion date 0% complete
Place of performance
Newark, NJ 07107, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Opioids, such as morphine, are potent analgesics commonly administered to perioperative and pregnant patients. A common adverse effect of opioids is pruritus (ITCH), which can be experienced by up to 85% of patients, depending on route of administration. Clinical management of opioid-induced pruritus includes pharmacotherapies such as antihistamines and opioid-receptor antagonists, which have variable efficacy and cause adverse effects such as sedation or reduced analgesia. Morphine and damgo are agonists of the Μ-opioid receptor (MOR; OPRM1), a GI-coupled G-protein coupled receptor (GPCR). Activation of the MOR decreases neuronal excitability via inhibitory GAI and GBG G- protein subunits which dissociate from each other and inhibit depolarization via interactions with various proteins. One mechanism by which MOR activation inhibits depolarization is inhibition of the nonselective cation channel transient receptor potential melastatin 3 (TRPM3) by GBG, which interacts with a peptide sequence encoded by TRPM3 exon 17. To study the physiological role of TRPM3 inhibition by GBG, we generated a mouse line without exon 17 of TRPM3 (TRPM3DEX17) and showed that this mouse line experiences significantly less ITCH in response to neuraxial morphine and intradermal damgo. Neuraxial-morphine-induced ITCH is thought to be caused by inhibition of inhibitory dorsal horn neurons expressing the endogenous Κ-opioid dynorphin (PDYN). These PDYN+ neurons tonically inhibit ITCH in the spinal cord and their inhibition leads to increased ITCH transmission (DISINHIBITION). In specific aim 1 of the proposal, we will use electrophysiology, elisa/biochemical assays, and behavioral studies in wild-type and genetically modified mice to determine the central mechanism by which TRPM3 inhibition contributes to opioid-induced ITCH. ITCH induced by intradermal injection of damgo is mediated by peripheral TRPV1+ nociceptors, indicating that neuraxial and systemic opioids induce ITCH via distinct mechanisms. Our findings suggest that both mechanisms may involve TRPM3 inhibition. In specific aim 2 of the proposal, we will use behavioral studies in wild-type and genetically modified mice to address the mechanisms by which TRPM3 inhibition in peripheral nociceptors contributes to opioid-induced ITCH. Understanding the mechanisms by which neuraxial and systemic opioids elicit severe ITCH is vital for generation of effective pharmacotherapies to improve the quality of life of patients receiving opioids. Our proposed experiments will not only contribute to the body of knowledge surrounding ITCH signaling but will also evaluate TRPM3 as a potential target for ITCH pharmacotherapies.

Transactions

Action Obligated Date
Amendment $0
Original award $34,818

Quick answers

Who received award F30NS141489?

F30NS141489 was awarded to Rutgers The State University Of New Jersey by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on December 1, 2026.

How much is award F30NS141489 worth?

$34,818 has been obligated on F30NS141489.

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