William Clarke, Ph.D.
Distinguished Teaching Professor, Department of Pharmacology
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, functional selectivity or biased agonism (the ability of different ligands that act at the same receptor to produce different responses) and allosterism. 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.). To study opioid receptor function and regulation in peripheral pain-sensing neurons, we utilize a complementary system that includes 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.
Field of Study: Pharmacology of drugs that act via 7-transmembrane-spanning receptors
Sub Field of Study: Mechanisms of peripheral opioid receptor-mediated antinociception
Relevant Diseases: Pain, Addiction, Mood Disorders
Research Techniques: Cell culture, signal transduction, pharmacology, confocal microscopy, immunohistochemistry, behavior, drug-receptor interactions, biochemistry
Publications
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Jacobs BA, Pando MM, Jennings EM, Jamshidi RJ, Zamora JC, Chavera TS, Clarke WP and Berg KA (2019) Signaling characteristics and functional regulation of delta opioid-kappa opioid receptor (DOP-KOP) heteromers in peripheral sensory neurons. Neuropharmacology 151:208-218. Jacobs BA, Pando MM, Jennings E, Chavera TA, Clarke WP and Berg KA (2018) Allosterism within delta Opioid-kappa Opioid Receptor Heteromers in Peripheral Sensory Neurons: Regulation of kappa Opioid Agonist Efficacy. Mol Pharmacol 93:376-386. Berg KA and Clarke WP (2018) Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity. Int J Neuropsychopharmacol 21:962-977. Sullivan LC, Chavera TA, Gao X, Pando MM and Berg KA (2017) Regulation of delta Opioid Receptor-Mediated Signaling and Antinociception in Peripheral Sensory Neurons by Arachidonic Acid-Dependent 12/15-Lipoxygenase Metabolites. J Pharmacol Exp Ther 362:200-209. LoCoco PM, Risinger AL, Smith HR, Chavera TS, Berg KA and Clarke WP (2017) Pharmacological augmentation of nicotinamide phosphoribosyltransferase (NAMPT) protects against paclitaxel-induced peripheral neuropathy. Elife6:e29626. Sullivan LC, Chavera TS, Jamshidi RJ, Berg KA and Clarke WP (2016) Constitutive Desensitization of Opioid Receptors in Peripheral Sensory Neurons. J Pharmacol Exp Ther 359:411-419. Jamshidi RJ, Sullivan LC, Jacobs BA, Chavera TA, Berg KA and Clarke WP (2016) Long-Term Reduction of Kappa Opioid Receptor Function by the Biased Ligand, Norbinaltorphimine, Requires c-Jun N-Terminal Kinase Activity and New Protein Synthesis in Peripheral Sensory Neurons. J Pharmacol Exp Ther 359:319-328. |
Grants
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| Funding Agency | NIH/NIDA |
| Title |
Pharmacological and behavioral effects of MCAM: a long-acting, μ opioid receptor antagonist for treatment of opioid overdose and opioid abuse disorder |
| Status | Active |
| Period | 5/15/19 - 5/31/22 |
| Role | Principal Investigator |
| Grant Detail |
The major goal of this work is to examine the pharmacological and functional properties of a long-acting mu opioid receptor antagonist, methocinnamox, that we hypothesize will be an improved treatment of opioid overdose (better than naloxone, the current drug) and may also be useful for prevention of opioid abuse and relapse. |
| Funding Agency | NIH/NIDA |
| Title | KOR agonist functional selectivity in peripheral sensory neurons |
| Status | Active |
| Period | 9/15/15 - 7/31/21 |
| Role | Principal Investigator |
| Grant Detail |
The major goal of this project is to perform structure-functional selectivity relationship studies for KOR agonists based upon U50488 and salvinorin-A as scaffolds and measuring drug efficacy at inhibition of adenylyl cyclase activity (Gαi response), activation of extracellular signal-regulated kinase (ERK), and activation of c-Jun N-terminal kinase (JNK) in peripheral sensory neurons. The hypothesis is that ligands with high efficacy for the Gαi pathway relative to ERK and JNK will have improved efficacy to produce analgesia in behavioral tests. |
| Funding Agency | Ed Nash Long Life Foundation |
| Title |
P7C3-A20: A novel drug to improve age-related deficits in vitality and cognition |
| Status | Active |
| Period | 12/1/2019 - 11/30/2021 |
| Role | Principal Investigator |
| Grant Detail |
The major goal of this work is to determine the effects of a novel neuroprotective agent, P7C3-A20, on vitality and cognition in aging rat. |
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 |