Neuropathic pain encompasses a range of painful conditions of diverse origins including diabetic neuropathy, post-herpetic neuralgia and nerve injuries after surgery. It includes pain following paraplegia, hypersensitivity to non-painful stimli (allodynia), for example after surgery or during migraine attacks, spontaneous pain, hyperalgesia and diffuse muscle tenderness of myofacial syndromes. Back pain, cancer pain and AIDS associated pain also qualify as neuropathic pain. Currently prescribed drugs for neuropathic pain are often addictive, are not effective for all patients and have various side effects including tolerance, addiction, sedation, liver toxicity. The financial burden from the los of productivity in the US alone numbers in the billions of dollars notwithstanding the misery these patients suffer. Recently, we have discovered a series of nonsedating alpha2/alpha3 BzR/GABA (A) agonists that are active against neuropathic pain as well as anxiety disorders and convulsions. These agents do not develop tolerance and are comprised of a privileged scaffold (imidazobenzodiazepine), the result of which has less chance for toxicity. Because they exhibit little or no efficacy at a1 and a5 subtypes, they will exhibit very little or no abuse potential. This research centers on the modification of these new agents to prolong duration of action in vivo and to provide better subtype selectivity at either a2 or a3 BzR/GABA(A)ergic subtypes. This would preclude the origin of side effects including sedation, ataxia, amnesia, tolerance and abuse potential. In addition, this work will help to establish which GABAerigc subtype in the spinal cord is the nociceptive target of choice. An eventual goal is to replace the addictive opioid analgesics with these safer, non addictive ligands for treatment of all types of neuropathic and inflammatory pain, in human populations.

Public Health Relevance

The design and development of new nonsedating, nonaddictive agents to treat neuropathic pain is under study. These agents are designed to treat diabetic neuropathy, post-herpetic neuralgia, phantom limb pain, pain from nerve injuries after surgery. This includes pain after paraplegia, hypersensitivity to non-painful stimuli (allodynia) and migraine attacks. It is felt these agents will also be effective in back pain, cancer pain and AIDS associated pain without the side effects of morphine (including addiction) or of COX-2 inhibitors (heart problems). There is a significant unmet need for new drugs to treat neuropathic pain. The financial burden from the loss of productivity in the US alone numbers in the billions of dollars, notwithstanding the misery these patients must endure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS076517-01A1
Application #
8435779
Study Section
Special Emphasis Panel (ZRG1-DDNS-C (01))
Program Officer
Babcock, Debra J
Project Start
2012-09-01
Project End
2016-06-30
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$318,422
Indirect Cost
$99,672
Name
University of Wisconsin Milwaukee
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
627906399
City
Milwaukee
State
WI
Country
United States
Zip Code
53201
Jahan, Rajwana; Stephen, Michael Rajesh; Forkuo, Gloria S et al. (2017) Optimization of substituted imidazobenzodiazepines as novel asthma treatments. Eur J Med Chem 126:550-560
Meyer, Mariah A A; Corcoran, Kevin A; Chen, Helen J et al. (2017) Neurobiological correlates of state-dependent context fear. Learn Mem 24:385-391
Batini?, Bojan; Santra?, Anja; Jan?i?, Ivan et al. (2017) Positive modulation of ?5 GABAA receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide. Int J Dev Neurosci 61:31-39
Fischer, Bradford D; Schlitt, Raymond J; Hamade, Bryan Z et al. (2017) Pharmacological and antihyperalgesic properties of the novel ?2/3 preferring GABAA receptor ligand MP-III-024. Brain Res Bull 131:62-69
Forkuo, Gloria S; Nieman, Amanda N; Yuan, Nina Y et al. (2017) Alleviation of Multiple Asthmatic Pathologic Features with Orally Available and Subtype Selective GABAA Receptor Modulators. Mol Pharm 14:2088-2098
McMurray, Katherine M J; Sidhu, Preetpal S; Cook, James M et al. (2017) Genetic and pharmacological manipulation of glyoxalase 1 regulates voluntary ethanol consumption in mice. Addict Biol 22:381-389
Holtyn, August F; Tiruveedhula, V V N Phani Babu; Stephen, Michael Rajesh et al. (2017) Effects of the benzodiazepine GABAA ?1-preferring antagonist 3-isopropoxy-?-carboline hydrochloride (3-ISOPBC) on alcohol seeking and self-administration in baboons. Drug Alcohol Depend 170:25-31
Witkin, J M; Cerne, R; Wakulchik, M et al. (2017) Further evaluation of the potential anxiolytic activity of imidazo[1,5-a][1,4]diazepin agents selective for ?2/3-containing GABAA receptors. Pharmacol Biochem Behav 157:35-40
McMurray, K M J; Ramaker, M J; Barkley-Levenson, A M et al. (2017) Identification of a novel, fast-acting GABAergic antidepressant. Mol Psychiatry :
Lewter, Lakeisha A; Fisher, Janet L; Siemian, Justin N et al. (2017) Antinociceptive Effects of a Novel ?2/?3-Subtype Selective GABAA Receptor Positive Allosteric Modulator. ACS Chem Neurosci 8:1305-1312

Showing the most recent 10 out of 68 publications