Rutgers New Jersey Medical School

mTOR, a new target for opioid-induced tolerance and hyperalgesia.

The aim of this project is to investigate whether and how mTOR, an enzyme controls the translation of most proteins, in spinal cord dorsal horn neurons participates in the induction and maintenance of opioid-induced tolerance and hyperalgesia. A novel mu opioid receptor-triggered PI3K/Akt-/mTOR pathway in dorsal horn neurons is to be identified in promoting morphine-induced spinal protein translation changes and associated morphine tolerance and hyperalgesia.

Supported by: NIH R01 DA033390, PI: Tao, YX

Notable Publications:

• Xu JT, Zhao J, Zhao X, Ligons D, Tiwari V, Lee CY, Atianjoh FE, Liang L, Zang W, Njoku D, Raja SN, Yaster M, Tao YX. Opioid receptor-triggered spinal mTORC1 activation contributes to morphine tolerance and hyperalgesia. J Clin Invest 124: 592-603, 2014.
• Xu Ji-Tian, Sun L, Lutz BM, Bekker A, Tao YX. Blocking spinal cord mTOR1 attenuates morphine-induced analgesic tolerance and hyperalgesia in rats with neuropathic pain. Transl Perioper & Pain Med 2(2):27-34, 2015.
• Lutz BM, Nia S, Xiong M, Tao YX, Bekker A. mTOR, a new potential target for chronic pain and opioid-induced tolerance and hyperalgesia. Mol Pain 11: 32, 2015

Epigenetic mechanisms of neuropathic pain: role of native Kv1.2 antisense RNA.

The goal of this work is to identify a new endogenous long non-coding RNA, named as Kv1.2 antisense RNA, for a voltage-dependent potassium channel mRNA, Kcna2, in the first-order sensory neurons of dorsal root ganglion. The project will evaluate whether this antisense RNA is involved in neuropathic pain genesis.

Supported by: NIH R01 NS 072206. PI: Tao YX

Notable Publications:

• Zhao X, Atianjoh FE, Zhang H, Tang Z, Zhao J, Liang L, Wang W, Guan X, Kao SC, Tiwari V, Hoffman PN, Cui H, Li M, Dong X, Tao YX. A native long noncoding RNA contributes to neuropathic pain by silencing Kcna2 in primary afferent neurons. Nat Neurosci 16 (2013) 1024-1031.
• Fan L, Guan X, Wang W, Zhao JY, Zhang H, Tiwari V, Hoffman PN Li, M, Tao YX. Impaired neuropathic pain and preserved acute pain in rats overexpressing voltage-gated potassium channel subunit Kv1.2 in primary afferent neurons. Mol Pain (2014) 10:8.
• Li Z, Gu X, Wu S, Sun L, Liang L, Cao J, Lutz BM, Bekker A, Zhang W, Tao YX. Dorsal root ganglion myeloid zinc finger protein 1 contributes to neuropathic pain after peripheral nerve trauma. Pain 156: 711-21, 2015.

Role of rostromedial tegmental nucleus in alcohol addiction.

The goal of this project has been to explore the role of rostromedial tegmental nucleus (RMTg) during alcohol consumptive behavior, with an emphasis on the GABAergic regulation of dopamine signaling in the ventral tegmental area. The aversive effects of alcoholism are a serious public health concern, and insight with respect to the RMTg, which has recently been identified as relevant in this context, could inform treatment strategies.

Supported by: NIH 1R01AA022292-01A1. PI: Ye JH

Notable Publications:

• Fu R, Zuo W, Gregor D, Li J, Grech D, Ye JH*. Pharmacological Manipulation of the Rostromedial Tegmental Nucleus Changes Voluntary and Operant Ethanol Self-administration in Rats. Alcoholism: Clinical and Experimental Research. 2016 Mar;40(3):572-82. PMID: 26876382;PMCID: PMC4775316.
• Guan YZ, Ye JH. Glycine blocks long-term potentiation of GABAergic synapses in the ventral tegmental area. Neuroscience. 2016;318:134-42. PMID: 26806277; PMCID: PMC4753108.
• Fu R, Chen X, Zuo W, Li J, Kang S, Zhou LH, Siegel A, Bekker A, Ye JH. Ablation of μ opioid receptor-expressing GABA neurons in rostromedial tegmental nucleus increases ethanol consumption and regulates ethanol-related behaviors. Neuropharmacology. 2016 PMID: 26921770.

Mechanisms of regulation of ethanol intake by lateral habenula.

The purpose of this study has been to examine the role of the lateral habenula (LHb) neurons in alcohol intake during alcohol withdrawal using a rat model. The project is motivated by a hypothesis that dis-function of LHb neurons contributes to excessive drinking via inhibiting dopamine transmission in the ventral tegmental area.

Supported by NIH, NIAAA 1R01AA021657-01A1. PI: Ye JH

Notable Publications:

• Zuo W, Fu R, Hopf FW, Xie G, Krnjević K, Li J, Ye JH*. Ethanol drives aversive conditioning through dopamine 1 receptor and glutamate receptor-mediated activation of lateral habenula neurons. Addict Biol. 2015 PMID: 26283508. PMCID: PMC4758919.
• Zuo W, Zhang Y, Xie G, Gregor D, Bekker A, Ye J-H*. Serotonin stimulates lateral habenula via activation of the postsynaptic serotonin 2/3 receptors and transient receptor potential channels. Neuropharmacology. 2016 PMID: 26471419;PMCID: PMC4681642.
• Xie G, Zuo W, Wu L, Li W, Wu W, Bekker A, Ye JH. 2016. Serotonin modulates glutamatergic transmission to neurons in the lateral habenula. Science Reports, accepted for publication

Multimodal Management of Acute Pain: The role of opioid adjuvants

The major therapeutic objective underlying the use of opioid adjuvants is to achieve a balance between increasing analgesic efficacy while minimizing adverse effects. Currently our group is studying the effects of perioperative administration of IV NSADs, IV Acetaminophen, as well as other non-opioid analgesics on stress responses and postoperative recovery. Our results suggest that NSAIDs modulates the stress and inflammatory responses as demonstrated by a decrease in the level of catecholamines, cortisol, and cytokines. In addition, all of the adjuvant therapies improve a quality of recovery and early postoperative outcomes.

Supported by Cumberland Pharmaceuticals and Mallinckrodt Pharmaceuticals

Notable Publications:

• Le V, Kurnutala L, Schiandicola J, Yarmush J, Eloy JD, Shapiro M, Bekker A. Premedication with intravenous ibuprofen improves recovery characteristics and stress response in adults undergoing laparoscopic cholecystectomy: A randomized controlled trial. Pain Medicine 2016; Published ahead of print, doi: 10.1093/pm/pnv113
• Singla N, Jahr J, Bekker A, Hale M, Royal M, Ang R, Davis J, Viscusi E. IV Acetaminophen: Efficacy of a single dose for postoperative pain after hip arthroplasty: subset data analysis of two unpublished randomized clinical trials. Amer J Therapeutics 2015, 22:2-10
• Radvansky B, Shah K, Parikh A, Sifonios A, Le V, Eloy JD. Role of ketamine in acute postoperative pain management. BioMed Res Int 2015, 749837

Epigenetic regulation of neuropathic pain: Role of DRG histone methyltransferase G9a

The aim of this project is to investigate whether dorsal root ganglion G9a contributes to pain hypersensitivity following peripheral nerve injury and whether and how peripheral nerve injury alters the expression of dorsal root ganglion G9a. We will also examine whether and how G9a participates in the nerve injury-induced down-regulation of MOR and KOR in the injured dorsal root ganglion, resulting in an increase in primary afferent neurotransmitter release.

Supported by: NIH R01 NS094664, PI: Tao, YX

Notable Publications:

• Liang L, Gu X, Zhao JY, Wu S, Miao X, Xiao J, Mo K, Zhang J, Lutz BM, Bekker A, Tao YX. G9a participates in nerve injury-induced Kcna2 downregulation in primary sensory neurons. Sci Rep 6:37704, 2016.
• Li Z, Mao Y, Liang L, Wu S, Yuan Y, Mo K, Mao Q, Cao J, Bekker A, Zhang W, Tao YX. Contribution of dorsal root ganglion C/EBPβ to peripheral nerve trauma-induced nociceptive hypersensitivity. Sci Signal 10 (2017) eaam5345.
• Liang L, Zhao JY, Gu X, Wu S, Mo K, Xiong M, Lutz BM, Bekker A, Tao YX. G9a inhibits CREB-triggered expression of mu opioid receptor in primary sensory neurons following peripheral nerve injury. Mol Pain. 12 (2016) 1-16.
• Zhang J, Miao X, Liang L, Wu S, Cao J, Tao B, Mao Q, Mo K, Lutz BM, Bekker A, Tao YX. Contribution of the histone methyltransferase SUV39H1 in dorsal root ganglion and spinal cord dorsal horn to neuropathic pain. Anesthesiology 125 (2016) 765-78.

Dissection of a new spinal cord circuits in pain sensation

The goal of this project is to define molecular, physiological, and anatomical properties of deep layer early RET+ inhibitory interneurons and to dissect neural circuits associated with deep layer early RET+ inhibitory interneurons. Functions of deep layer early RET+ inhibitory interneurons in acute pain and chronic pain will also be examined.

Supported by: NIH R01 NS094224, PI: Tao, YX

Notable Publications:

• Cui L, Miao X, Liang L, Abdus-Saboor I, Olson W, Fleming MS, Ma M, Tao YX, Luo W. Identification of Early RET+ Deep Dorsal Spinal Cord Interneurons in Gating Pain. Neuron 91: 1-17, 2016.

Role of endothelin in sickle cell disease (SCD)

This work is to examine whether local inhibition or genetic knockdown of ETA receptor in nociceptors attenuate chronic pain and hypoxia/reoxygenation-induced exacerbated pain in SCD mice and whether the amount of ET-1 in peripheral tissues and the level of ETA receptor in nociceptors increase in SCD mice. The potential mechanisms of how ET-1 and ETA receptor are involved SCD pain will also be explored.

Supported by: NIH U01HL117684, Subcontract PI: Tao, YX

Notable Publications:

• Lutz BM, Meiler SE, Bekker A, Tao YX. Current updates on sickle cell disease-associated chronic pain. Transl Perioper & Pain Med 1(2015) 8-17.

Epigenetic mechanism of nerve injury-induced Kv1.2 downregulation in DRG neurons

This is a F31 training grant and is to examine whether and how DNMT3a contributes to the nerve injury-induced downregulation of Kv1.2 in the injured DRG and whether DRG DNMT3a affects Kv current and neuronal excitability in DRG and contributes to pain hypersensitivity under neuropathic pain conditions.

Supported by: NIH F31NS092310, PI: Lutz, B. Mentor: Tao, YX

Notable Publications:

• Zhao JY, Liang L, Gu X, Li Z, Wu S, Sun L, Atianjoh FE, Feng J, Mo K, Jia S, Lutz BM, Bekker A, Nestle EJ, Tao YX. DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons. Nat Commun 8:14712, 2017.
• Sun L, Zhao JY, Gu X, Liang L, Wu S, Mo K, Feng J, Guo W, Zhang J, Bekker A, Zhao X, Nestler EJ, Tao YX. Nerve injury-induced epigenetic silencing of opioid receptors controlled by DNMT3a in primary afferent neurons. Pain 158:1153-65, 2017.