The long-term objective of this proposal is to understand the signaling mechanisms underlying desensitization of MOR1D-GRPR crosstalk, which is required for opioid-induced itch. Spinal or epidural opioid-induced itch is a prevalent side effect in pain management and the underlying molecular and cellular mechanisms are poorly understood. MOR1D, a Gi protein-coupled mu opioid receptor isoform, mediates morphine-induced itch through cross-activation of gastrin-releasing peptide receptor (GRPR), an itch-specific receptor in the spinal cord. This cross-talk leads to morphine-induced itch signaling We found that phosphorylation is a major mechanism underlying a rapid desensitization of MOR1D-GRPR signaling.
In Aim 1, we will determine the effect of morphine-induced phosphorylation on MOR1D-GRPR signaling.
Aim 2 will determine the function of GRK2/arrestin2 in MOR1D-GRPR desensitization.
Aim 3 will examine the role of PKC in MOR1D-GRPR desensitization and test the hypothesis that PKC and GRK2/arrestin2 function independently. We will use a combination of mouse genetics, molecular, cellular, biochemical, biophysical, electrophysiological and behavioral approaches to address these questions. Our studies will improve understanding of the signaling mechanism underlying desensitization of MOR1D-GRPR, and may yield important information for novel therapeutics for treating opioid-induced itch without compromising opioid analgesia.
Opioid-induced itch is a prevalent side effect of spinal or epidural opioid analgesia and remains poorly understood. We will examine molecular mechanisms of desensitization of opioid-induce itch in the spinal cord. Our studies may lead to a better understanding of how opioid-induced itch is terminated, and may aid in designing better therapies for managing opioid-induced itch without compromising opioid analgesia.
| Munanairi, Admire; Liu, Xian-Yu; Barry, Devin M et al. (2018) Non-canonical Opioid Signaling Inhibits Itch Transmission in the Spinal Cord of Mice. Cell Rep 23:866-877 |
| Barry, Devin M; Munanairi, Admire; Chen, Zhou-Feng (2018) Spinal Mechanisms of Itch Transmission. Neurosci Bull 34:156-164 |
| Wan, Li; Jin, Hua; Liu, Xian-Yu et al. (2017) Distinct roles of NMB and GRP in itch transmission. Sci Rep 7:15466 |
| Oetjen, Landon K; Mack, Madison R; Feng, Jing et al. (2017) Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch. Cell 171:217-228.e13 |
| Yu, Yao-Qing; Barry, Devin M; Hao, Yan et al. (2017) Molecular and neural basis of contagious itch behavior in mice. Science 355:1072-1076 |
