Chronic pain is a disabling disease that affects a large proportion of the U.S. population. An intriguing pain syndrome that results from trauma, often with associated peripheral nerve injury, is sympathetically maintained pain (SMP). SMP is characterized by pain and hyperalgesia to mechanical and thermal stimuli that are dependent on sympathetic innervation of the painful region. Based on advances made during the last granting period, a model has been developed to explain the pathophysiology and pharmacology of SMP. The proposed studies will test a tenet of the model that a1 adrenoceptors develop in peripheral tissues such that the release of norepinephrine from the sympathetic terminals activates nociceptors and leads to pain. Parallel studies will be done in patients and in a recently developed nerve injury paradigm for SMP in rats. The proposed clinical and behavioral studies will address two questions: (1) Is a peripheral a-adrenergic receptor the culprit in SMP? To answer this question, the pain and hyperalgesia produced by intradermally administered alpha1-, alpha2- and beta-adrenergic agonists and a adrenergic blockers will be compared in normal subjects and in patients with SMP or with sympathetically independent pain (SIP). The adrenergic pharmacology of SMP will be further characterized with behavioral studies in rat using a partial sciatic nerve injury paradigm. Earlier studies have indicated that the pain behavior in this rat paradigm is sympathetically maintained. The proposed behavioral studies will also provide information about the site of interaction between the sympathetic efferents and the somatic afferent fibers. (2) Can alpha-adrenergic drugs be used in the diagnosis of SMP? During the past granting period, a diagnostic test for SMP was developed based on the pain relief obtained during intravenous administration of phentolamine. In the proposed studies, the relief of pain and hyperalgesia in SMP following topical administration of clonidine will be investigated as a less invasive diagnostic tool. The proposed studies will lead to a better understanding of the pathophysiology and pharmacology of SMP and to the development of more specific diagnostic tests and pharmacological therapies for alleviating the pain and hyperalgesia in this debilitating pain state.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS026363-06
Application #
2265904
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1989-04-01
Project End
1996-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
6
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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
Finnerup, Nanna B; Attal, Nadine; Haroutounian, Simon et al. (2015) Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 14:162-73
Yang, Fei; Zhang, Tong; Tiwari, Vinod et al. (2015) Effects of Combined Electrical Stimulation of the Dorsal Column and Dorsal Roots on Wide-Dynamic-Range Neuronal Activity in Nerve-Injured Rats. Neuromodulation 18:592-7; discussion 598
Smith, Sherika N; Paige, Candler; Velazquez, Kandy T et al. (2015) Injury-specific promoters enhance herpes simplex virus-mediated gene therapy for treating neuropathic pain in rodents. J Pain 16:283-90

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