GPR160 de-orphanization reveals critical roles in neuropathic pain in rodents
Gina L.C. Yosten, … , Willis K. Samson, Daniela Salvemini
Gina L.C. Yosten, … , Willis K. Samson, Daniela Salvemini
Published January 30, 2020
Citation Information: J Clin Invest. 2020;130(5):2587-2592. https://doi.org/10.1172/JCI133270.
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Concise Communication Neuroscience

GPR160 de-orphanization reveals critical roles in neuropathic pain in rodents

Abstract

Treating neuropathic pain is challenging and novel non–opioid-based medicines are needed. Using unbiased receptomics, transcriptomic analyses, immunofluorescence, and in situ hybridization, we found that the expression of the orphan GPCR Gpr160 and GPR160 increased in the rodent dorsal horn of the spinal cord following traumatic nerve injury. Genetic and immunopharmacological approaches demonstrated that GPR160 inhibition in the spinal cord prevented and reversed neuropathic pain in male and female rodents without altering normal pain response. GPR160 inhibition in the spinal cord attenuated sensory processing in the thalamus, a key relay in the sensory discriminative pathways of pain. We also identified cocaine- and amphetamine-regulated transcript peptide (CARTp) as a GPR160 ligand. Inhibiting endogenous CARTp signaling in spinal cord attenuated neuropathic pain, whereas exogenous intrathecal CARTp evoked painful hypersensitivity through GPR160-dependent ERK and cAMP response element–binding protein (CREB). Our findings de-orphanize GPR160, identify it as a determinant of neuropathic pain and potential therapeutic target, and provide insights into its signaling pathways. CARTp is involved in many diseases including depression and reward and addiction; de-orphanization of GPR160 is a major step forward understanding the role of CARTp signaling in health and disease.

Authors

Gina L.C. Yosten, Caron M. Harada, Chris Haddock, Luigino Antonio Giancotti, Grant R. Kolar, Ryan Patel, Chun Guo, Zhoumou Chen, Jinsong Zhang, Timothy M. Doyle, Anthony H. Dickenson, Willis K. Samson, Daniela Salvemini

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Figure 2

GPR160 inhibition attenuated and reversed neuropathic pain.

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GPR160 inhibition attenuated and reversed neuropathic pain. (A) CCI-indu...
(A) CCI-induced and (B) spared nerve injury–induced (SNI-induced) mechano-allodynia in male rats were prevented by daily i.th. siGpr160 (A, n = 6; B, n = 4), but not sieGfp control (A, n = 7; B, n = 4). (C) CCI-induced mechano-allodynia in male rats was reversed by i.th. siGpr160, but not sieGfp (n = 3/group). CCI-induced (D) mechano-allodynia (n = 6/group) and (E) cold-allodynia (n = 3/group) in male rats was reversed with i.th. GPR160 Ab, but not with nonspecific IgG. (F) Intrathecal GPR160 Ab (n = 4), but not IgG (n = 5), reversed CCI-induced mechano-allodynia in female rats. (G) Intrathecal GPR160 Ab or IgG (n = 7/group) in normal male rats had no effect on tail-flick nociceptive responses. (H and I) Intrathecal CARTp Ab (H, n = 11; I, n = 3), but not IgG (H, n = 8; I, n = 4), reversed CCI-induced mechano-allodynia in male mice (H) and rats (I). When compared with baseline, i.th. GPR160 Ab (n = 5) attenuated neuronal responses to punctate mechanical stimuli (J), but not ongoing neuronal activity (K) in spinal nerve ligation (SNL), but not sham, rats. No effects on neuronal responses to punctate mechanical stimuli (L) or ongoing neuronal activity (M) were observed with IgG (n = 4) in naive rats. Data are expressed as mean ± SD (A–I) or mean ± SEM (J–M) and analyzed by 2-tailed, 2-way repeated-measures ANOVA with Bonferroni’s multiple-comparisons test (A–F and H–L) or 2-tailed t test (G and M). *P < 0.05 versus day 0 (D0), #P < 0.05 versus D7, and †P < 0.05 versus baseline (BL). PWT, paw withdrawal threshold.