Publications

@article{Sanjel2026,

title = {OPRM1/MRGPRX1 heterodimers drive opioid-induced itch through a peripheral mechanism},

author = {Babina Sanjel and Diwas Rawal and Myeong Ryeo Kim and Wook-Joo Lee and Kwang Won Jeong and Won-Sik Shim},

doi = {10.1186/s12929-026-01238-x},

issn = {1423-0127},

year  = {2026},

date = {2026-12-00},

urldate = {2026-12-00},

journal = {J Biomed Sci},

volume = {33},

number = {1},

publisher = {Springer Science and Business Media LLC},

abstract = {<jats:title>Abstract</jats:title>

                  <jats:sec>

                    <jats:title>Background</jats:title>

                    <jats:p>Opioid-induced itch is a common and distressing side effect of opioid analgesics, yet its underlying mechanisms remain poorly understood. While central µ-opioid receptor (OPRM1) signaling has been implicated, emerging evidence suggests that peripheral mechanisms also contribute, although their specific roles have not been clearly defined.</jats:p>

                  </jats:sec>

                  <jats:sec>

                    <jats:title>Methods</jats:title>

                    <jats:p>We investigated the interaction between OPRM1 and the itch-specific receptor MRGPRX1 in sensory neurons using bimolecular fluorescence complementation (BiFC), calcium and cAMP imaging, siRNA knockdown, and pharmacological inhibition assays. Behavioral assays in mice were conducted to assess scratching responses. We also employed immunohistochemistry, RT-qPCR, and ELISA to evaluate gene and protein expression levels in dorsal root ganglia (DRG) and skin tissues, including a mouse model of atopic dermatitis (AD).</jats:p>

                  </jats:sec>

                  <jats:sec>

                    <jats:title>Results</jats:title>

                    <jats:p>

                      OPRM1 formed heterodimers with MRGPRX1 in HEK293T cells and sensory neurons, triggering a signaling switch from Gα

                      <jats:sub>i/o</jats:sub>

                      -mediated cAMP inhibition to Gα

                      <jats:sub>q/11</jats:sub>

                      -driven calcium mobilization upon activation with DAMGO or endogenous opioids. This heterodimerization elicited robust intracellular calcium responses and scratching behavior in mice, which were attenuated by OPRM1 or MRGPRX1 antagonists. In the AD mouse model, increased OPRM1 expression and β-endorphin levels were observed in DRG neurons, correlating with heightened scratching and calcium responses. In contrast, although the δ-opioid receptor (OPRD1) associated with MRGPRX2, it did not trigger mast cell degranulation, suggesting a limited contribution to peripheral itch signaling.

                    </jats:p>

                  </jats:sec>

                  <jats:sec>

                    <jats:title>Conclusions</jats:title>

                    <jats:p>Our findings identify a novel peripheral mechanism of opioid-induced itch mediated by OPRM1/MRGPRX1 heterodimers in sensory neurons. This receptor complex promotes calcium signaling and itch behavior, distinct from central or mast cell–dependent pathways. Targeting this heterodimer may offer new therapeutic strategies to alleviate opioid-induced itch without impairing analgesia.</jats:p>

                  </jats:sec>},

keywords = {Calcium imaging, Itch, MRGPRX1, Opioid, OPRM1},

pubstate = {published},

tppubtype = {article}

}

@article{InKim2023,

title = {FSLLRY-NH2, a protease-activated receptor 2 (PAR2) antagonist, activates mas-related G protein-coupled receptor C11 (MrgprC11) to induce scratching behaviors in mice},

author = {Hye In Kim and Gi Baek Lee and Da Eun Song and Babina Sanjel and Wook-Joo Lee and Won-Sik Shim},

doi = {10.1016/j.lfs.2023.121786},

issn = {0024-3205},

year  = {2023},

date = {2023-07-00},

urldate = {2023-07-00},

journal = {Life Sciences},

volume = {325},

publisher = {Elsevier BV},

abstract = {Aims: Protease-activated receptor 2 (PAR2), a type of G protein-coupled receptor (GPCR), plays a significant role in pathophysiological conditions such as inflammation. A synthetic peptide SLIGRL-NH2 (SLIGRL) can activate PAR2, while FSLLRY-NH2 (FSLLRY) is an antagonist. A previous study showed that SLIGRL activates both PAR2 and mas-related G protein-coupled receptor C11 (MrgprC11), a different type of GPCR expressed in sensory neurons. However, the impact of FSLLRY on MrgprC11 and its human ortholog MRGPRX1 was not verified. Hence, the present study aims to verify the effect of FSLLRY on MrgprC11 and MRGPRX1.



Methods: The calcium imaging technique was applied to determine the effect of FSLLRY in HEK293T cells expressing MrgprC11/MRGPRX1 or dorsal root ganglia (DRG) neurons. Scratching behavior was also investigated in wild-type and PAR2 knockout mice after injecting FSLLRY.



Key findings: It was surprisingly discovered that FSLLRY specifically activates MrgprC11 in a dose-dependent manner, but not other MRGPR subtypes. Furthermore, FSLLRY also moderately activated MRGPRX1. FSLLRY stimulates downstream pathways including Gαq/11, phospholipase C, IP3 receptor, and TRPC ion channels to evoke an increase in the intracellular calcium levels. The molecular docking analysis predicted that FSLLRY interacts with the orthosteric binding pocket of MrgprC11 and MRGPRX1. Finally, FSLLRY activated primary cultures of mouse sensory neurons, and induced scratching behaviors in mice.



Significance: The present study has revealed that FSLLRY is capable of triggering itch sensation through activation of MrgprC11. This finding highlights the importance of considering the unexpected activation of MRGPRs in future therapeutic approaches aimed at the inhibition of PAR2.},

keywords = {Calcium imaging, FSLLRY, Itch, MrgprC11, MRGPRX1, PAR2, Scratching behavior},

pubstate = {published},

tppubtype = {article}

}

@article{Sanjel2019,

title = {BAM8-22 and its receptor MRGPRX1 may attribute to cholestatic pruritus},

author = {Babina Sanjel and Han-Joo Maeng and Won-Sik Shim},

doi = {10.1038/s41598-019-47267-5},

issn = {2045-2322},

year  = {2019},

date = {2019-12-00},

urldate = {2019-12-00},

journal = {Sci Rep},

volume = {9},

number = {1},

publisher = {Springer Science and Business Media LLC},

abstract = {Pruritus is an unexpected symptom observed in cholestasis and its mechanism is still unclear. Here, we show that bovine adrenal medulla (BAM) 8–22, an endogenous itch-inducing peptide, could be involved in cholestatic pruritus. It was found that bile duct ligation (BDL) mice, an obstructive cholestasis model, showed increased spontaneous scratching behaviour. Importantly, the mRNA level of proenkephalin, a precursor polypeptide of BAM8-22, was significantly increased in the skin of BDL mice. Furthermore, the mRNA level of Mrgprx1, which encodes a receptor for BAM8-22, was significantly increased in the dorsal root ganglia (DRG) of BDL mice. This was further confirmed by elevation of intracellular calcium levels upon BAM8-22 treatment in primarily-cultured DRG neurons. In addition, BDL mice showed augmented scratching behaviour by BAM8-22, indicating enhanced activity of MRGPRX1. Moreover, the skin homogenate of BDL mice induced elevation of intracellular calcium levels through MRGPRX1. Finally, among the various bile acids, chenodeoxycholic acid significantly increased proenkephalin transcription in a human keratinocyte cell line (HaCaT). In conclusion, cholestatic pruritus could be attributed in part to enhanced action of both BAM8-22 in the skin and its receptor MRGPRX1 in sensory neurons.},

keywords = {Animal model, Calcium imaging, Cholestasis, Dorsal root ganglia, MrgprC11, MRGPRX1, Scratching behavior},

pubstate = {published},

tppubtype = {article}

}