Understanding the mechanisms that underlie opioid-induced analgesic tolerance and hyperalgesia is important for developing novel therapeutic strategies to achieve more effective pain management. The changes in dorsal horn neuronal plasticity that occur after chronic opioid exposure are believed to underlie the induction and maintenance of opioid-induced tolerance and hyperalgesia. Mammalian target of rapamycin (mTOR), a serine-threonine protein kinase, controls protein translation via phosphorylation of specific downstream effectors, such as 4E-BP1 and S6K1. Our preliminary work indicates that mu receptor/PI3K/Akt- mediated activation of dorsal horn mTOR participates in the formation of neuronal plasticity through mTOR- triggered initiation of protein translation during chronic morphine exposure. These novel discoveries suggest that dorsal horn mTOR activation is required for the development and maintenance of morphine-induced tolerance and hyperalgesia. This proposal will determine whether and how mTOR and its downstream effectors are activated in dorsal horn neurons under chronic morphine exposure and whether and how this activation contributes to the development and maintenance of morphine-induced analgesic tolerance and hyperalgesia.
In Specific Aim 1, we will examine (a) whether mTOR, S6K1, 4E-BP1, PI3K, and Akt are activated through mu receptor activation in dorsal horn following repeated morphine injections;(b) whether PI3K and Akt mediate mu receptor-triggered activation of mTOR, S6K1, and 4E-BP1 in dorsal horn neurons during chronic morphine exposure;and (c) whether the PI3K/Akt/mTOR pathway is activated in mu receptor-expressing and nociceptive dorsal horn neurons following repeated morphine injection.
In Specific Aim 2, we will define whether spinal mu receptor-dependent activation of the PI3K/Akt/mTOR pathway contributes to mechanism of morphine tolerance and hyperalgesia through mTOR-triggered dorsal horn protein synthesis. We will examine (a) time-dependent increases in translation initiation activity, nascent protein synthesis, and some known tolerance-associated key proteins in dorsal horn neurons following chronic morphine exposure and (b) whether these increases could be blocked by inhibition of spinal mu receptor-triggered activation of the PI3K/Akt/mTOR pathway.
In Specific Aim 3, we will determine whether spinal mTOR and the translation initiation that it triggers are required for the development and maintenance of morphine-induced tolerance and hyperalgesia. The effects of pharmacologic inhibition of spinal mTOR, genetic knockdown of spinal mTOR and S6K1, or over- expression of dorsal horn 4E-BP1 on the development and maintenance of morphine-induced tolerance and hyperalgesia will be examined. The proposed studies will provide major conceptual advances to our understanding of the molecular mechanism of morphine-induced analgesic tolerance and hyperalgesia. Because mTOR inhibitors are FDA-approved drugs, our studies may also have a strong potential clinical application in treating and/or preventing opioid-induced analgesic tolerance and hyperalgesia.

Public Health Relevance

Development of opioid-induced analgesic tolerance and hyperalgesia is a significant clinical challenge when patients are given prolonged or repeated opioid treatment for moderate to severe pain. Understanding molecular mechanisms that underlie opioid-induced analgesic tolerance and hyperalgesia is important to achieving more effective pain treatment. The proposed studies will test a novel hypothesis that mu receptor- mediated activation of the PI3K/Akt/mTOR pathway contributes to the development and maintenance of morphine-induced analgesic tolerance and hyperalgesia through mTOR-triggered initiation of protein translation in spinal dorsal horn.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
7R01DA033390-02
Application #
8738282
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Rapaka, Rao
Project Start
2013-02-15
Project End
2017-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
2
Fiscal Year
2014
Total Cost
$334,727
Indirect Cost
$109,502
Name
Rutgers University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
07103
Zhao, Jian-Yuan; Liang, Lingli; Gu, Xiyao et al. (2017) DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons. Nat Commun 8:14712
Xu, Bo; Cao, Jing; Zhang, Jun et al. (2017) Role of MicroRNA-143 in Nerve Injury-Induced Upregulation of Dnmt3a Expression in Primary Sensory Neurons. Front Mol Neurosci 10:350
Sun, Linlin; Zhao, Jian-Yuan; Gu, Xiyao et al. (2017) Nerve injury-induced epigenetic silencing of opioid receptors controlled by DNMT3a in primary afferent neurons. Pain 158:1153-1165
Wang, Shaocheng; Li, Qixian; Fang, Hongwei et al. (2017) Spinal cord stimulation versus other therapies in patients with Refractory Angina: A meta-analysis. Transl Perioper Pain Med 2:31-41
Khariv, Veronika; Ni, Li; Ratnayake, Ayomi et al. (2017) Impaired sensitivity to pain stimuli in plasma membrane calcium ATPase 2 (PMCA2) heterozygous mice: a possible modality- and sex-specific role for PMCA2 in nociception. FASEB J 31:224-237
Li, Zhisong; Mao, Yuanyuan; Liang, Lingli et al. (2017) The transcription factor C/EBP? in the dorsal root ganglion contributes to peripheral nerve trauma-induced nociceptive hypersensitivity. Sci Signal 10:
Zhang, Jun; Liang, Lingli; Miao, Xuerong et al. (2016) Contribution of the Suppressor of Variegation 3-9 Homolog 1 in Dorsal Root Ganglia and Spinal Cord Dorsal Horn to Nerve Injury-induced Nociceptive Hypersensitivity. Anesthesiology 125:765-78
Nwagwu, Chibueze D; Sarris, Christina; Tao, Yuan-Xiang et al. (2016) Biomarkers for Chronic Neuropathic Pain and their Potential Application in Spinal Cord Stimulation: A Review. Transl Perioper Pain Med 1:33-38
Sun, Linlin; Lutz, Brianna Marie; Tao, Yuan-Xiang (2016) The CRISPR/Cas9 system for gene editing and its potential application in pain research. Transl Perioper Pain Med 1:22-33
Cui, Lian; Miao, Xuerong; Liang, Lingli et al. (2016) Identification of Early RET+ Deep Dorsal Spinal Cord Interneurons in Gating Pain. Neuron 91:1137-1153

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