The ability to treat neuropathic pain (NP) remains unsatisfactory, as many patients experience pain despite taking prescribed medications. Although opioids are effective against NP, their clinical usefulness is limited by their central nervous system effects (i.e., sedation, cognitive dysfunction, and tolerance). Using the L5 spinal nerve ligation model in rodents, we found that loperamide, a peripherally acting opioid, alleviates behavioral signs of NP. In addition, we reported that enhancing <-opioid receptor (MOR) expression in primary afferents, using HSV viral vectors, results in a leftward shift in the analgesic dose-response curve of loperamide. Thus, opioid receptors in the peripheral nervous system present a valuable target for the treatment of NP in humans. Surprisingly, repetitive administration of loperamide induces peripheral opioid tolerance. In this proposal, we aim to modulate the interactions of MORs and -opioid receptors (DORs) in the peripheral nervous system to enhance peripheral opioid analgesia and to attenuate peripheral opioid tolerance. We hypothesize that after nerve injury, the functional interactions between MORs and DORs are crucial for both the observed peripheral opioid antihyperalgesic effects and the development of peripheral opioid tolerance. Specifically, we hypothesize that: 1) DOR agonists enhance the analgesic effects of peripheral MOR agonists in opioid-naove animals with NP, 2) chronic administration of a MOR agonist switches DORs from an enhancing to an inhibitory role, thereby contributing to peripheral opioid tolerance, and 3) the development of tolerance is due to the formation of MOR-DOR heterodimers, and peripheral opioid tolerance in NP can be prevented or reversed by inhibiting heterodimerization. A broad range of strategies will be used to test these hypotheses, including behavioral, electrophysiological, Ca2+ imaging, and molecular biological methods. We will test whether concurrent activation of peripheral MORs and DORs will result in enhanced antihyperalgesia in opioid-naove rodents with NP (Aim 1) and whether repeated administration of peripheral MOR agonist switches the DOR into a """"""""negative modulator"""""""" of MOR function, resulting in attenuation of peripheral opioid antihyperalgesia (Aim 2). To study the role of DOR and DOR-MOR heterodimerization in opioid antihyperalgesia and peripheral opioid tolerance, innovative virus-mediated gene transfer strategies will be used to suppress DOR expression and to inhibit DOR-MOR heterodimerization by expressing a dimer-deficient DOR (Aim 3). In addition, a novel small peptide that blocks DOR-MOR heterodimerization will be studied for its effect on opioid tolerance. The results of these studies will provide new insights into the mechanisms that underlie the peripheral pain-reducing effects of opioids in NP and the mechanisms that underlie peripheral opioid tolerance. Furthermore, the use of virus mediated gene transfer and small cell permeable peptide inhibitors of heterodimerization are viable pre-clinical approaches to develop novel therapeutic strategies for the treatment of NP and opioid tolerance.

Public Health Relevance

Pain persisting after injury to nerves, neuropathic pain, is a significant public health issue that affects up to 7% of the population and impairs quality of life considerably. Currently available therapies have limited clinical usefulness because are not always fully effective at relieving pain and can cause undesirable effects such as drowsiness, altered cognitive function, and tolerance. The proposed research will help identify targets for the development of new drugs for neuropathic pain that may lead to pain relief with minimal adverse effects.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Chen, Daofen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
Tiwari, Vinod; Anderson, Michael; Yang, Fei et al. (2018) Peripherally Acting ?-Opioid Receptor Agonists Attenuate Ongoing Pain-associated Behavior and Spontaneous Neuronal Activity after Nerve Injury in Rats. Anesthesiology 128:1220-1236
He, Shao-Qiu; Xu, Qian; Tiwari, Vinod et al. (2018) Oligomerization of MrgC11 and ?-opioid receptors in sensory neurons enhances morphine analgesia. Sci Signal 11:
Finnerup, Nanna B; Haroutounian, Simon; Baron, Ralf et al. (2018) Neuropathic pain clinical trials: factors associated with decreases in estimated drug efficacy. Pain 159:2339-2346
Klein, Amanda H; Mohammad, Husam K; Ali, Rabiah et al. (2018) Overexpression of ยต-Opioid Receptors in Peripheral Afferents, but Not in Combination with Enkephalin, Decreases Neuropathic Pain Behavior and Enhances Opioid Analgesia in Mouse. Anesthesiology 128:967-983
Colloca, Luana; Ludman, Taylor; Bouhassira, Didier et al. (2017) Neuropathic pain. Nat Rev Dis Primers 3:17002
Yang, Fei; Xu, Qian; Shu, Bin et al. (2016) Activation of cannabinoid CB1 receptor contributes to suppression of spinal nociceptive transmission and inhibition of mechanical hypersensitivity by A?-fiber stimulation. Pain 157:2582-2593
Tiwari, Vinod; Yang, Fei; He, Shao-Qiu et al. (2016) Activation of Peripheral ?-opioid Receptors by Dermorphin [D-Arg2, Lys4] (1-4) Amide Leads to Modality-preferred Inhibition of Neuropathic Pain. Anesthesiology 124:706-20
Yang, Fei; Zhang, Chen; Xu, Qian et al. (2015) Electrical stimulation of dorsal root entry zone attenuates wide-dynamic-range neuronal activity in rats. Neuromodulation 18:33-40; discussion 40
Smith, Terika P; Schlenz, Alyssa M; Schatz, Jeffrey C et al. (2015) Modulation of pain in pediatric sickle cell disease: understanding the balance between endothelin mediated vasoconstriction and apelin mediated vasodilation. Blood Cells Mol Dis 54:155-9
Li, Z; He, S-Q; Tseng, P-Y et al. (2015) The inhibition of high-voltage-activated calcium current by activation of MrgC11 involves phospholipase C-dependent mechanisms. Neuroscience 300:393-403

Showing the most recent 10 out of 88 publications