| First Author | Pereira PJ | Year | 2015 |
| Journal | J Neurosci | Volume | 35 |
| Issue | 49 | Pages | 16272-81 |
| PubMed ID | 26658875 | Mgi Jnum | J:227985 |
| Mgi Id | MGI:5704231 | Doi | 10.1523/JNEUROSCI.2310-15.2015 |
| Citation | Pereira PJ, et al. (2015) GRPR/PI3Kgamma: Partners in Central Transmission of Itch. J Neurosci 35(49):16272-81 |
| abstractText | The gastrin-releasing peptide (GRP) and its receptor (GRPR) are important components of itch transmission. Upstream, but not downstream, aspects of GRPR signaling have been investigated extensively. We hypothesize that GRPR signals in part through the PI3Kgamma/Akt pathway. We used pharmacological, electrophysiological, and behavioral approaches to further evaluate GRPR downstream signaling pathways. Our data show that GRP directly activates small-size capsaicin-sensitive DRG neurons, an effect that translates into transient calcium flux and membrane depolarization ( approximately 20 mV). GRPR activation also induces Akt phosphorylation, a proxy for PI3Kgamma activity, in ex vivo naive mouse spinal cords and in GRPR transiently expressing HEK293 cells. The intrathecal injection of GRP led to intense scratching, an effect largely reduced by either GRPR antagonists or PI3Kgamma inhibitor. Scratching behavior was also induced by the intrathecal injection of an Akt activator. In a dry skin model of itch, we show that GRPR blockade or PI3Kgamma inhibition reversed the scratching behavior. Altogether, these findings are highly suggestive that GRPR is expressed by the central terminals of DRG nociceptive afferents, which transmit itch via the PI3Kgamma/Akt pathway. SIGNIFICANCE STATEMENT: Itch is the most common symptom of the skin and is related to noncutaneous diseases. It severely impairs patients' quality of life when it becomes chronic and there is no specific or effective available therapy, mainly because itch pathophysiology is not completely elucidated. Our findings indicate that the enzyme PI3Kgamma is a key central mediator of itch transmission. Therefore, we suggest PI3Kgamma as an attractive target for the development of new anti-pruritic drugs. With this study, we take a step forward in our understanding of the mechanisms underlying the central transmission of itch sensation. |
