William Clarke, Ph.D.
Professor, Pharmacology
Chemotherapy-induced peripheral neuropathy
Research in our lab is focused on understanding the cellular and molecular mechanisms of drug efficacy (the ability of a drug to produce a response). Together with my long-time collaborator, Dr. Kelly Berg, our work has employed a combination of quantitative pharmacological, biochemical, molecular, cellular and behavioral approaches. We are especially interested in ligand-independent (constitutive) receptor activity, inverse agonism, and functional selectivity or biased agonism (the ability of different ligands that act at the same receptor to produce different responses). We are also interested in how these pharmacological parameters differ with cell phenotype and cell physiological state. For the past several years our studies have centered upon the regulation and function of peripheral opioid receptors expressed by peripheral pain-sensing neurons and their role as potential targets for safer treatments for pain. Inhibition of these pain-sensing neurons can produce powerful analgesia. Opioid drugs that are modified to be peripherally-restricted so that they do not enter the CNS would be effective analgesics for some forms of pain (post-surgical, inflammatory, etc.) that involve activity of the peripheral pain-sensing neurons but would be devoid of the serious adverse effects that are due to opioid action on receptors expressed in the CNS (respiratory depression, addiction, abuse, sedation, etc.). We utilize a complementary system to study opioid receptor function and regulation in peripheral pain-sensing neurons that include the study of peripheral sensory neurons, derived from the trigeminal and dorsal root ganglia, in culture and well as in vivo in behavioral assays of pain. The combination of ex vivo (primary neuronal cultures) and in vivo studies is a powerful approach that allows for rigorous, quantitative, pharmacological analyses of cellular signaling systems and assessment of the physiological relevance of findings obtained from ex vivo studies. Additional studies that utilize this complementary system include projects to understand the cellular and molecular mechanisms that underlie a medication-overuse headache and that underlie the protection against the development of chemotherapy-induced peripheral neuropathy by the novel stimulator of nicotinamide phosphoribosyltransferase (NAMPT), P7C3-A20.
Related diseases: Pain, headache, chemotherapy-induced peripheral neuropathy
Techniques: pharmacology, primary cell culture, cell signaling, immunohistochemistry, behavior
Publications
Abstract |
| LoCoco PM, Risinger AL, Mooberry SL, Berg KA, Clarke WP. The neuroprotective agent, P7C3-A20, prevents paclitaxel-induced allodynia in the rat; 2015 Nov. (Presented at the Society for Neuroscience Meeting). |
| LoCoco PM, Chavera TA, Scofield HO, Jamshidi RJ, Mooberry SL, Berg KA, Clarke WP. Subpopulations of peripheral sensory neurons are differentially sensitive to the microtubule-targeting agent, paclitaxel; 2015 Jan. (Presented at the Chemotherapy-Induced Peripheral Neuropathy Symposium, Santa Barbara, CA). |
| McGuire BA, Chavera TA, Clarke WP, Berg KA. Allosteric interactions within delta opioid receptor ? kappa opioid receptor (DOR-KOR) heteromers in peripheral sensory neurons; 2014 Nov. (Presented at the Experimental Biology Meeting, San Diego, CA). |
| LoCoco PM, Chavera TA, Scofield HO, Jamshidi RJ, Mooberry SL, Berg KA, Clarke WP. Subpopulations of peripheral sensory neurons are differentially sensitive to the microtubule-targeting agent, paclitaxel; 2014 Nov. (Presented at the Society for Neuroscience Meeting). |
| Sullivan LC, Jamshidi RJ, LoCoco PM, Berg KA, Clarke WP. Age-related differences in the sensitivity to allodynia produced by TRP receptor agonists; 2014 Nov. (Presented at the Society for Neuroscience Meeting). |
| LoCoco PM, Villarreal G, Dybdal-Hargreaves NF, Mooberry SL, Berg KA, Clarke WP. The neuroprotective agent, P7C3-A20, prevents paclitaxel-induced peripheral neuropathy in the rat; 2014 Oct. (Presented at UTHSCSA Pharmacology/Neuroscience Graduate Student Symposium). |
| Jamshidi RJ, McGuire BA, Sullivan LC, Chavera TA, Clarke WP, Berg KA. Unique regulation of peripheral kappa opioid receptor (KOR) function by the protean ligand, norBNI; 2014 Mar. (Presented at the Behavior, Biology, and Chemistry Conference, San Antonio, TX). |
| LoCoco PM, Scofield HO, Chavera TA, Mooberry SL, Berg KA, Clarke WP. The microtubule-targeting agent, paclitaxel, differentially damages bradykinin (B2) receptor-expressing nociceptors San Antonio TX; 2013 Oct. (Presented at UTHSCSA Pharmacology/Neuroscience Graduate Student Symposium). |
Journal Article |
| Sullivan LC, Chavera TA, Jamshidi RJ, Berg KA, Clarke WP. Constitutive desensitization of opioid receptors in peripheral sensory neurons J Pharmacol Exp Ther 2016 Jan;359(3):411-419. |
| Sullivan LC, Clarke WP, Berg KA. Atypical antipsychotics and inverse agonism at 5-HT2 receptors Curr Pharm Des 2015 Jan;21(26):3732-3738. |
| Broselid S, Berg KA, Chavera TA, Kahn R, Clarke WP, Olde B, Leeb-Lundberg LM. G protein-coupled receptor 30 (GPR30) forms a plasma membrane complex with membrane-associated guanylate kinases (MAGUKs) and protein kinase A-anchoring protein 5 (AKAP5) that constitutively inhibits cAMP production J Biol Chem 2014 Jan;289(32):22117-22127. |
| Rowan MP, Berg KA, Roberts JL, Hargreaves KM, Clarke WP. Activation of estrogen receptor alpha enhances bradykinin signaling in peripheral sensory neurons of female rats J Pharmacol Exp Ther 2014 Jan;349(3):526-532. |
Grants
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Federal |
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| Funding Agency | ASPET |
| Title | ASPET Fellowship Program for Undergraduate Students |
| Status | Active |
| Period | 6/2007 - Present |
| Role | Principal Investigator |
| Grant Detail | |
| Funding Agency | NIH/NIA |
| Title | Aging, peripheral pain and analgesia |
| Status | Active |
| Period | 2/2015 - 1/2018 |
| Role | Principal Investigator |
| Grant Detail | We propose to evaluate the effect of aging on the function and regulation of peripheral, pain-sensing neurons and opioid receptor systems expressed by these neurons. Our ultimate goal is to develop analgesics with improved efficacy and safety for use in the elderly population |
| Funding Agency | NIH/NGMS |
| Title | Regulation of Kappa opioid receptor-mediated signaling and peripheral analgesia |
| Status | Active |
| Period | 1/2014 - 11/2017 |
| Role | Principal Investigator |
| Grant Detail | The major goal of this project is to study the regulation of kappa opioid receptor (KOR) signaling systems by the MAPKinases, ERK and JNK, as well as acute desensitization of KOR agonist signaling in peripheral sensory neurons, using primary cultures of adult rat sensory neurons and a behavioral model of nociception |
| Funding Agency | NIH/NIDA |
| Title | Regulation of DOR-KOR heteromer formation in pain-sensing neurons |
| Status | Active |
| Period | 9/2014 - 8/2017 |
| Role | Principal Investigator |
| Grant Detail | We propose to validate approaches to disrupt the formation or function of delta-kappa opioid receptor heteromers expressed by pain-sensing neurons in vivo and ex vivo. |
Education
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| Year | Degree | Discipline | Institution |
| 1984 | PhD | Physiology | Wayne State University School of Medicine Detroit , MI |
| 1979 | MS | Biology | Northeastern University Boston , MA |
| 1974 | BS | Chemistry | Boston College Boston , MA |
| Postdoctoral Fellowship | Pharmacology | Mount Sinai School of Medicine New York , NY |