Research Assistant Professor
Prolonged opioid or cannabinoid analgesic treatment leads to a gradual decline in pain relief and thus, clinicians need to use steadily increasing drug doses in the management of severe chronic pain. Higher analgesic doses on the other hand, are more likely to lead to serious side effects and drug addiction. The overall goal of our research is to develop longer acting antinociceptive agents that produce fewer side effects during long-term treatment of chronic pain. To accomplish this goal we use molecular and cellular approaches to determine how opioids (such as morphine) and cannabinoids (such as the active components of marijuana) interact with their membrane receptors and activate cellular signal transduction and to identify the molecular mechanisms leading to altered cellular signaling upon long-term opioid and cannabinoid treatment.
Interestingly, while acute administration of opioids (or cannabinoids acting at the neuronal (CB1) cannabinoid receptor type) efficiently relieves pain, sustained exposure to these drugs causes a paradoxical increase in the sensitivity of patients to painful (hyperalgesia) and even to normally painless (allodynia) stimuli. We hypothesize that this increased pain sensitivity greatly contributes to the necessity for increased analgesic drug doses in the treatment of chronic pain. Our research projects focus on the cellular events that lead to regulation of the “gain� in pain signal transduction in the spinal cord upon sustained opioid and cannabinoid treatment.
Sustained morphine-mediated compensatory adaptations in the primary sensory neurons:
Earlier we have shown that sustained opioid agonist treatment leads to a sensitization of cellular adenylyl cyclase enzymes toward excitatory agents (AC superactivation) in a Raf-1-dependent manner in recombinant model cells. Currently we investigate the physiological role of this molecular mechanism in sustained morphine-mediated augmentation of a pain neurotransmitter release from primary sensory neurons in vitro (see Fig. 1) and exploring the utility of novel compounds (such as small interfering RNA (siRNA)) to attenuate Raf-1-mediated AC superactivation in vivo , in the spinal cord of morphine-treated experimental animals. We expect that data from this research project will facilitate the development of novel pharmaceutical agents that prevent the development of pain sensitization and thus reduce antinociceptive tolerance during long-term analgesic treatment.
Figure 1.
The role of spinal microglia in sustained morphine-mediated pain sensitization:
Resident non-neuronal cells (glia) in the central nervous system were shown to play an important role in the regulation of pain sensitivity in inflammatory and neurodegenerative conditions. Interestingly, sustained opioid analgesic treatment also activates CNS glia and glial inhibitors were shown to attenuate sustained morphine-mediated pain sensitization. We are currently investigating the utility of a novel pharmacological target for suppression of spinal glial activation during sustained morphine treatment. We have demonstrated earlier that co-administration of morphine with a peripheral cannabinoid receptor (CB2)-selective agonist attenuates hyperalgesia and allodynia produced by morphine withdrawal in experimental animals. We hypothesize that this effect is due to activation of spinal microglial CB2 receptors. We are currently investigating the molecular mechanism of CB2 receptor signaling in spinal microglia and its interplay with sustained opioid-mediated signal transduction (see Fig. 2). This research is expected to facilitate the design of novel bi-functional pharmaceutical agents that exhibit increased efficacy and prolonged analgesic action in the treatment of chronic pain.
Fig. 2.
Tumati S, Yamamura HI, St John PA, Vanderah TW, Roeske WR, Varga EV. Sustained cannabinoid agonist treatment augments CGRP release in a PKA-dependent manner. Neuroreport. 2009 Apr 21. [Epub ahead of print]
Tumati S, Largent-Milnes T, Yamamura HI, Vanderah TW, Roeske WR, Varga EV: Intrathecal Raf-1-selective siRNA attenuates sustained morphine-mediated thermal hyperalgesia. Eur J Pharmacol, 601(1-3):207-8, 2008.
Yue X, Tumati S, Navratilova E, Stropova D, St John PA, Vanderah TW, Roeske WR, Yamamura HI, Varga EV: Sustained morphine treatment augments basal CGRP release from cultured primary sensory neurons in a Raf-1 dependent manner. Eur J Pharmacol. 584(2-3):272-7, 2008.
Georgieva, T., Devanathan, S., Stropova, D., Park, C.K., Salamon, Z., Tollin, G., Hruby, V.J., Roeske, W.R., Yamamura, H.I. and Varga, E.: Unique agonist-bound cannabinoid CB(1) receptor conformations indicate agonist specificity in signaling. Eur. J. Pharmacol, 581:19-29, 2008.
Navratilova E, S Waite, D Stropova, MC Eaton, ID Alves, VJ Hruby, WR Roeske, HI Yamamura, EV Varga: Quantitative evaluation of human delta opioid receptor desensitization using the operational model of drug action. Mol Pharmacol. 71(5):1416-26, 2007.
Varga EV, K Hosohata, D Borys, E Navratilova, A Nylen, TW Vanderah, F Porreca, WR Roeske, HI Yamamura: Antinociception depends on the presence of G protein gamma2-subunits in brain. Eur J Pharmacol. 508(1-3):93-8. 2005.
Alves ID, KA Ciano, V Boguslavski, EV Varga, Z Salamon, HI Yamamura, VJ Hruby, G Tollin: Selectivity, cooperativity, and reciprocity in the interactions between the delta-opioid receptor, its ligands, and G-proteins. J Biol Chem. 279(43):44673-82, 2004.
Varga EV, Rubenzik MK, Stropova D, Sugiyama M, Grife V, Hruby VJ, Rice KC, Roeske WR, Yamamura HI: Converging protein kinase pathways mediate adenylyl cyclase superactivation upon chronic delta-opioid agonist treatment. J Pharmacol Exp Ther, 306: 109-115, 2003.
Rubenzik M, Varga EV, Stropova D, Roeske WR, Yamamura HI: Expression of alpha-transducin in Chinese hamster ovary cells stably transfected with the human delta-opioid receptor attenuates chronic opioid agonist-induced adenylyl cyclase superactivation. Mol Pharmacol 60:1076-1082, 2001.