Srinivasa N Raja, MD 
Professor, Division of Pain Medicine

Eellan Sivanesan, MD
Assistant Professor, Division of Pain Medicine

Shao-Qiu He, PhD
Instructor, Division of Pain Medicine

Qin Zheng, PhD
Instructor, Division of Pain Medicine,

Neil Ford, PhD
Post-doctoral Fellow

Jing Liu, PhD
Post-doctoral Fellow

Ankit Uniyal, PhD
Post-doctoral Fellow

Xiang Cui, PhD
Post-doctoral Fellow

Guangwu Zhu, MS
Lab manager

Mechanistic Study of Pain Inhibition by Activation of Non-nociceptive Afferent Fibers
This is a multidisciplinary project to study the neurobiological mechanisms that underlie pain inhibition by electrical stimulation of low-threshold afferent Aβ-fibers (Aβ-ES). We further examine an innovative strategy of “circuitry-specific enhancement of pain inhibition” to improve Aβ-ES pain therapies, such as dorsal column stimulation.

Mrgs, A New Target for the Treatment of Neuropathic Pain
We will use complementary animal behavioral, electrophysiological, and molecular biological approaches to better assess the therapeutic utility of MrgprX1 agonist for the treatment of neuropathic pain and to understand the cellular and molecular mechanisms underlying the drug action. This study may identify a new pain-specific treatment target and lead to a novel mechanism-based approach to the treatment of neuropathic pain.

Birth Tissue Products for Non-opioid Treatment of Post-surgical Pain
This multidisciplinary study aims to discover and validate the use of human birth tissues (e.g., amniotic membrane, umbilical cord) as a novel non-opioid treatment of post-surgical pain, and to unravel the dual mode of anti-pain action.

Developing Novel Direct Current Stimulation Technology for Precision Pain Treatment
Neural prostheses can deliver reliable and efficient functional excitation of the nervous system to enable technology such as cochlear implants, retinal implants, pacemakers, spinal cord stimulators, and deep brain stimulators. The central goal of this project is to advance the technology toward achieving efficient suppression of the nervous system and to improve the application of neural prostheses for the treatment of chronic pain.

Synergizing Computational and Biological Approaches to Develop an Integrated Model of the Closed-Loop Pain System
The proposed program involves developing a computer modeling framework of the closed-loop pain system that enables tractable analysis of pain transmission to the brain in healthy and pathological conditions and the modulatory effects of neurostimulation.

Pre-clinical Study of Subliminal High Density Stimulation for Pain Treatment
We will compare the inhibitory actions of subliminal high-density stimulation and those of conventional spinal cord stimulation on neuropathic pain-related behavior in rats to reveal spinal segmental mechanisms that may underlie the pain relief induced by subliminal high-density stimulation in nerve-injured rats.

1. Guan Y, Borzan J, Meyer RA, Raja SN. Windup in dorsal horn neurons is modulated by endogenous spinal µ-opioid mechanisms. Neurosci. 2006: 26(16): 4298-4307.
2. Guan Y, Johanek LM, Hartke TV, Shim B, Tao YX, Ringkamp M, Meyer RA, Raja SN. Peripherally acting mu-opioid receptor agonist attenuates neuropathic pain in rats after L5 spinal nerve injury. Pain. 2008; 138(2):318-329.
3. Seal RP, WangX, Guan Y, Raja SN, Woodbury CJ, Basbaum AI, Edwards RH. Unmyelinated low threshold mechanoreceptors are required for injury-induced mechanical hypersensitivity. Nature. 2009; 462 (7273): 651-655. 
4. Liu Q, Tang Z, Surdenikova L, Kim S, Patel KN, Kim A, Ru F, Guan Y, Weng HJ, Geng Y, Undem BJ, Kollarik M, Chen ZF, Anderson DJ, Dong X. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell. 2009; 139(7): 1353-1365.
5. Guan Y, Liu Q, Tang Z, Raja SN, Anderson DJ, Dong X. Mas-related G-protein-coupled receptors inhibit pathological pain in mice. Natl. Acad. Sci. U. S. A, 2010; 107 (36): 15933-15938.   
6. Guan Y, Wacnik PW, Yang F, Carteret AF, Chung CY, Meyer RA, Raja SN. Spinal cord stimulation-induced analgesia: electrical stimulation of dorsal column and dorsal roots attenuates dorsal horn neuronal excitability in neuropathic rats. Anesthesiology. 2010; 113(6):1392-405.  
7. Han L, Ma C, Liu Q, Weng H, Cui Y, Tang Z, Kim Y, Nie H, Qu L, Patel KN, Li Z, McNeil B, He S-Q, Guan Y, Xiao B, LaMotte R, Dong  A subpopulation of nociceptors specifically linked to itch. Nature Neuroscience. 2012; 16(2):174-182.  
8. Shechter R, Yang F, Xu Q, Cheong Y-K, He S-Q, Sdrulla A, Carteret AF, Wacnik PW, Dong X, Meyer RA, Raja SN, Guan Y. Conventional and kilohertz-frequency spinal cord stimulation produces intensity- and frequency-dependent pain inhibition in a rat model of neuropathic pain. Anesthesiology. 2013;119(2): 422-432.   
9. He S-Q, Yang F, Perez F, Xu Q, Shechter R, Cheong YK, Carteret AF, Dong X, Sweitzer, SM, Raja SN, Guan Y. Tolerance to the anti-allodynic effects of the peripherally acting opioid, loperamide hydrochloride, develops in nerve-injured rats. Pain. 2013; 154 (11):2477-2486.  
10. He S-Q, Li Z, Chu Y-X, Han L, Xu Q, Li M, Yang F, Liu Q, Tang Z, Wang Y, Hin N, Tsukamato T, Slusher B, Tiwari V, Shechter R, Wei F, Raja SN, Dong X, Guan Y. MrgC agonism at central terminals of primary sensory neurons inhibits neuropathic pain. 2014; 155 (3):534-544.   
11. Li Z, He S-Q, Xu Q, Yang F, Tiwari V, Liu Q, Tang Z, Han L, Chu Y-X, Wang Y, Hin N, Tsukamato T, Slusher B, Guan X, Wei F, Raja SN, Dong X, Guan Y. Activation of MrgC receptor inhibits N-type calcium channels in small-diameter primary sensory neurons in mice. Pain. 2014; 155 (8):1613-1621.  
12. Weng H, Patel KN, Jeske NA, Bierbower SM, Zou W, Tiwari V, Zheng Q, Tang Z, Mo G, Wang Y, Geng Y, Zhang J, Guan Y,  Akopian A, Dong X. Tmem100 is a regulator of TRPA1-TRPV1 complex and contributes to persistent pain. Neuron. 2015; 85(4):833-846.
13. Sdrulla AD, Xu Q, He S-Q, Tiwari V, Yang F, Zhang C, Shechter R, Raja SN, Wang Y, Dong X, Guan Y. Electrical stimulation of low-threshold afferent fibers induces a prolonged synaptic depression in lamina II dorsal horn neurons to high-threshold afferent inputs in mice. 2015; 156(6):1008-1017.
14. Tiwari V, Yang F, He S-Q, Shechter R, Zhang C, Shu B, Zhang T, Tiwari V, Wang Y, Dong X, Guan Y, Raja SN. Activation of Peripheral μ-opioid Receptors by Dermorphin [D-Arg2, Lys4] (1-4) Amide Leads to Modality-preferred Inhibition of Neuropathic Pain. Anesthesiology. 2016; 124(3):706-720. Co-corresponding author.  
15. Yang F, Xu Q, Shu B, Tiwari V, He SQ, Vera-Portocarrero LP, Dong X, Linderoth B, Raja SN, Wang Y, Guan Y. Activation of cannabinoid CB1 receptor contributes to suppression of spinal nociceptive transmission and inhibition of mechanical hypersensitivity by Aβ-fiber Pain. 2016; 157(11):2582-2593.
16. Kim YS, Anderson M, Park K, Zheng Q, Agarwal A, Gong C, Saijilafu Young L, He S-Q, LaVinka PC, Zhou F, Bergles D, Hanani M, Guan Y, Spary DC, Dong X. Coupled activation of primary sensory neurons contributes to chronic pain. Neuron. 2016; 91(5):1085-1096.
17. Sun SH, Xu Q, Guo C, Guan Y, Liu Q, Dong X. Leaky gate model: intensity-dependent coding of pain and itch in spinal cord. Neuron. 2017; 93(4):840-853.  
18. Li Z, Tseng P-Y, Tiwari V, Xu Q, He SQ, Wang Y, Zheng Q, Han L, Wu Z, Blobaum AL, Cui Y, Tiwari V, Sun S, Cheng Y, Huang-Lionnet J, Geng Y, Xiao B, Peng J, Hopkins CR, Raja SN, Guan Y, Dong X. Targeting human Mas-related G-protein–coupled receptor X1 to inhibit persistent pain. Natl. Acad. Sci. U. S. A. 2017; 114(10): 1996-2005. Co-corresponding author.    
19. Yang F, Anderson M, He S, Stephens K, Zheng Y, Chen ZY, Raja SN, Aplin, F, Guan Y, Fridman G. Differential expression of voltage-gated sodium channels in afferent neurons renders selective neural block by ionic direct current. Science Advances. 2018; Apr 11;4(4):eaaq1438. doi: 10.1126/sciadv.aaq1438. Co-corresponding author.
20. Tiwari V, Anderson M, Yang F, Tiwari V, Zheng Q, He S-Q, Zhang T, Shu B, Chen XM, Grenald S, Stephens K, Chen Z, Dong X, Raja SN, Guan Y. Peripherally Acting μ-Opioid Receptor Agonists Attenuate Ongoing Pain-associated Behavior and Spontaneous Neuronal Activity after Nerve Injury in Rats. 2018 Jun; 128(6):1220-1236.
21. He SQ, Xu Q, Tiwari V, Yang, F, Anderson M, Chen ZY, Grenald S., Raja SN, Dong X, Guan Y. Oligomerization of MrgC11 and μ-opioid Receptors in Sensory Neurons Enhances Morphine Analgesia. Science Signaling. 2018 Jun 19;11(535). pii: eaao3134.
22. Stephens K, Chen Z, Sivanesan E, Raja SN, Linderoth B, Taverna SD, Guan Y. RNA-seq of Spinal Cord from Nerve-injured Rats after Spinal Cord Stimulation. Molecular Pain. 2018 Jan-Dec;14:1744806918817429.  
23. Zhu S, Zhu J, Zhen G, Hu Y, An S, Li Y, Zheng Q, Chen Z, Yang Y, Wan M, Skolasky RL, Cao Y, Wu T, Gao B, Yang M, Gao M, Kuliwaba J, Ni S, Wang L, Wu C, Findlay D, Eltzching HK, Ouyang HW, Crane J, Zhou FQ, Guan Y, Dong X, Cao X. Subchondral one osteoclasts induce sensory innervation and osteoarthritis pain. Journal Clinical Investigation. 2018; Dec 11. pii: 121561. 
24. Yang F, Duan WR, Huang Q, Chen Z, Ford N, Gao X, Sivanesan E, Sarma SV, Vera-Portocarrero LP, Linderoth B, Raja SN, Guan Y. Modulation of spinal nociceptive transmission by sub-sensory threshold spinal cord stimulation in rats after nerve injury. Neuromodulation. 2019 Jun 4.
25. Tiwari V, Tiwari V, He S-Q, Zhang T, Raja SN, Dong X, Guan  Mas-related G protein-coupled receptors offer potential new targets for pain therapy.  Adv Exp Med Biol. 2016; 904:87-103. 
26. Chakravarthy K, Richter H, Christo PJ, Williams K, Guan Y. Spinal cord stimulation for treating chronic pain: Reviewing preclinical and clinical data on paresthesia-free high-frequency therapy. Neuromodulation. 2018 Jan;21(1):10-18.
27. Sivanesan E, Maher D, Raja SN, Linderoth B, Guan Y. Supraspinal Mechanisms of Spinal Cord Stimulation for Modulation of Pain: Five Decades of Research and Prospects for the Future.   Anesthesiology. 2019 Apr;130(4):651-665. 
28. Liu S, Huang Q, He S-Q, Chen Z, Gao X, Ma D, Duan W, Ford N, Yang F, Chen X, Raja SN, Hao D, Guan Y. Dermorphin [D-Arg2, Lys4] (1-4) amide inhibits below-level heat hypersensitivity in mice after contusive thoracic spinal cord injury. Pain. 2019; 60:2710-2723. doi: 10.1097/j.pain.0000000000001671.
29. Sivanesan E, Stephens KE, Huang Q, Chen Z, Ford N, Duan W, He S-Q, Gao X, Linderoth B, Raja SN, Guan Y. Spinal Cord Stimulation Prevents Paclitaxel-induced Mechanical and Cold Hypersensitivity and Modulates Spinal Gene Expression in Rats. Pain Reports. 2019 Sep 12;4(5):e785.
30. Tiwari V, He S-Q, Huang Q, Liang L, Yang F, Chen Z, Tiwari V, Fujita W, Devi L.A., Dong X, Guan Y, Raja SN.  Activation of µ-δ Opioid Receptor Heteromers Inhibits Neuropathic Pain Behavior in Rodents. Pain. 2019 Dec 9. doi: 10.1097/j.pain.0000000000001768.    
31. Yang F, Duan WR, Huang Q, Chen Z, Ford N, Gao X, Sivanesan E, Sarma SV, Vera-Portocarrero LP, Linderoth B, Raja SN, Guan Y. Modulation of spinal nociceptive transmission by sub-sensory threshold spinal cord stimulation in rats after nerve injury. 2020 Jan;23(1):36-45.   
32. Ni S, Ling Z, Wang X, Cao Y, Wu T, Deng R, Crane JL, Skolask R, Demehril S, Zhen G, Jain A, Wu P, Pan D, Hu B, Lyu X, Li Y, Chen H, Qi H, Guan Y, Dong X, Wan M, Zou X, Lu H, Hu J, Cao Sensory innervation in porous endplates by Netrin-1 from osteoclasts mediates PGE2-induced spinal hypersensitivity in mice. Nature Communications. 2019 Dec 10;10(1):5643.  
33. Zhu JX, Zhen G, An S, Wang X, Wan M, Li Y, Chen Z, Guan Y, Dong X, Hu Y, Cao X. Aberrant Subchondral 1 Osteoblastic Metabolism Modifies NaV1.8 for Elife. 2020 May 22;9:e57656
34. Shu, B, He S-Q, Guan Y. Spinal Cord Stimulation Enhances Microglial Activation in the Spinal Cord of Nerve-injured Rats. Neurosci Bull. 2020 Sep 5. doi: 10.1007/s12264-020-00568-6.
35. Duan W, Huang Q, Yang F, He S-Q, Guan Y. Spinal cord stimulation attenuates below-level mechanical hypersensitivity in rats after thoracic spinal cord injury. 2021 Jan;24(1):33-42. doi: 10.1111/ner.13248. Epub 2020 Aug 8.
36. Gao X, Han S, Huang Q, He S-Q, Ford N, Zheng Q, Chen Z, Yu S, Dong X, Guan Y. Calcium imaging in population of dorsal root ganglion neurons unravels novel mechanisms of visceral pain sensitization and referred somatic hypersensitivity. 2021 Apr 1;162(4):1068-1081.   
37. Huang Q, Ford N, Gao X, Chen Z, Guo R, Raja S.N., Guan Y, He S-Q.  Ubiquitin-mediated receptor degradation contributes to development of tolerance to MrgC agonist-induced pain inhibition in neuropathic rats.   2021 Apr 1;162(4):1082-1094. doi: 10.1097/j.pain.0000000000002119.  
38. Sun Q, Zhen G, Li TP, Guo Q, Li Y, Su W, Xue P, Wang X, Wan M, Guan Y, Dong X, Li S, Cai M, Cao X. Parathyroid hormone attenuates osteoarthritis pain by remodeling subchondral bone in mice. 2021 Mar 1;10:e66532.
39. Stephens KE, Zhou W, Renfro Z, Ji Z, Ji H, Guan Y, Taverna SD.  Global gene expression and chromatin accessibility of the peripheral nervous system in animal models of persistent pain. J Neuroinflammation. 2021 Aug 26;18(1):185. Co-corresponding author.  
40. Xue P, Wang S, Lyu X, Wan M, Li X, Ma L, Ford NC, Li Y, Guan Y, Ding W, Cao X.  PGE2/EP4 skeleton interoception activity reduces vertebral endplate porosity and spinal pain with low-dose celecoxi Bone Research. 2021 Aug 2;9(1):36
41. Xu Q, Ford N.C., He S-Q, Huang Q, Anderson M, Chen Z, Yang F, Crawford L.K., Caterina M.J. Guan Y, Dong X. Astrocytes contribute to pain gating in the spinal cord. Science Advances. 2021. Nov 5;7(45):eabi6287. doi: 10.1126/sciadv.abi6287. Epub 2021 Nov 3. Co-corresponding author.  
42. Ford N.C., Barpujari A, He S-Q, Huang Q, Zhang C, Dong X, Guan Y, Raja SN. Role of primary sensory neurone cannabinoid type-1 receptors in painand the analgesic effects of the peripherally acting agonist CB-13 in mice. Br J Anaesth. 2021 Nov 26:S0007-0912(21)00690-5.  Co-corresponding author.  
43. North RB, Lempka SF, Guan Y, Air EL, Poree LR, Shipley J, Arle J, Rigoard P, Thomson S. Glossary of neurostimulation terminology: A collaborative NF, IoN, and INS project. 2021 Dec 18: S1094-7159(21)06185-7
44. Berhane I, Hin N, Thomas AG, Huang Q, Zhang C, Veeravalli V, Wu Y, Ng J, Alt J, Rojas C, Hihara H, Aoki M, Yoshizawa K, Nishioka T, Suzuki S, He S-Q, Peng Q, Guan Y, Dong X, Raja SN, Slusher BS, Rais R, Tsukamoto T. Thieno[2,3-d]pyrimidine-Based Positive Allosteric Modulators of Human Mas-Related G Protein-Coupled Receptor X1 (MRGPRX1). J Med Chem. 2022 Feb 4.    
45. Chen Z, Huang Q, Song X, Ford N, Zhang C, Xu Q, Lay M, He S-Q, Dong X, Hanani M, Guan Y.  Purinergic signaling between neurons and satellite glial cells of mouse dorsal root ganglia modulates neuronal excitability in vivo.  2022 Aug 1;163(8):1636-1647. 
46. Chen Z, Zhang C, Song X, Cui X, Liu J, Ford N, He S-Q Zhu G, Dong X, Hanani M, Guan Y. BzATP activates satellite glial cells and increases the excitability of dorsal root ganglia neurons in vivo. Cells. 2022 Jul 23;11(15):2280.
47. Zhang C, Hu MW, Wang X, Cui X, Liu J, Huang Q, Cao X, Zhou F, Qian J , He S-Q, Guan Y. scRNA-sequencing reveals subtype-specific transcriptomic perturbations in DRG neurons of Pirt-EGFPf mice in neuropathic pain condition. Elife. 2022 Oct 20;11:e76063.