Molecular Pharmacology

Two major areas of research interests are: 1) molecular mechanisms underlying pain perception and identify novel targets for analgesics and 2) the role of transient receptor potential (TRP) channels in diabetes.  A variety of transient receptor potential (TRP) channels have been cloned.  They are classified as TRP Classical (TRPC), TRP Vanilloid (TRPV), TRP Melastatin (TRPM), TRP Ankyrin (TRPA) and TRP Polycystin (TRPP).  TRP channels respond to temperature, touch, pain, osmolarity, pheromones, taste and other stimuli.  The research efforts are dedicated to study the characteristics of these channels and determine their role in diseases.  The structure and function of these channels are being studied using electrophysiological, immunihisto/cytochemical, molecular biological and biochemical techniques.  The studies will be carried out at the level of a single molecule, single cell, whole organ and whole anima.  Refractory chronic pain is a major problem especially in terminally ill patients.  Treatment with morphine is currently the only available option, which causes significant side effects, ranging from sedation to respiratory depression leading to premature death.  Resiniferatoxin (RTX), a potent agonist of TRPV1 exhibits unique properties that can be utilized to treat chronic pain conditions.   Intrathecal administration of RTX potently and selectively activates TRPV1 causing a depolarization block in the short-term, and ablation TRPV1 expressing central nerve terminals of the sensory neuron in the long-term at the level of the spinal cord.  Preventing nociceptive transmission at the level of the spinal cord usintg RTX will be a useful strategy in chronic, debilitating and intractable pain arising from large and inaccessible areas, such as malignancies of internal organs and bone.  The prevalence of diabetes has reached epidemic proportions,.  Diabetes is the leading cause of kidney failure and blindness in the US and accounts for more than 60% of the non-traumatic lower limb amputations due to diabetic peripheral neuropathy (DPN).  DPN is characterized by altered thermal, mechanical and chemical sensitivities.  TRP channels, TRPV1, TRPV4 and TRPA1 are implicated in inflammatory thermal and mechanical sensation.  Using modes of diabetes, we study the expression and function of nociceptive TRP channels and consider them as targets of intervention for symptoms associated with DPN.  Insulin secretion requires the generation of ATP in response t increased glucose levels and block of ATP sensitive potassium channels which depolarizes the beta cells and causes influx of calcium.  During the generation of ATP, reactive oxygen species (ROS) are generated and excess production of ROX causes pancreatic beta cell death.  We are exploring the possibility of increasing intracellular Ca2+ by activating TRP channels expressed in beta cells and preventing excessive oxidative stress by reducing ATP production and preserving beta cells.

Recent Publications

Samineni V, Premkumar LS, and Faingold CL. Post-ictal analgesia in genetically epilepsy-prone rats is induced by audiogenic seizures and involves cannabinoid receptors in the periaqueductal gray, Brain Res. 1389:177-183, 2011.

Walia V, Yang Y, Cao D, Cheng J, Rao K, Hollier B, Mani S, Sun M., Premkumar L, and Elble RC.  2011. Loss of breast epithelial marker hCLCA2 promotes epithelial to mesenchymal transition and metastasis. Oncogene, in press.