My research focuses on the transmission and control of "pain " messages. I have been studying the neuronal circuits that underlie the production of pain, combining several approaches that range from cellular and molecular biology to virology, pharmacology and behavior. In order to dissect the nociceptive circuitry, I developed a novel genetic approach (ZW transgenic mouse) that uses transneuronal transport of the anterograde tracer, wheat germ agglutinin (WGA) to study the central circuits that arise from primary afferent pain fibers and how they are modified after tissue or nerve injury. The key feature of the transgene that I have engineered is that the expression of the tracer can be controlled both spatially and temporally. Paralleling these studies, I also developed a new viral approach to study the inputs of anatomically distinct spinal cord nociceptive projection neurons. This approach involves the targeting of the expression of a virally-driven Cre recombinase to projection neurons so as to control the neuronal populations in which the replication of a Cre-dependent viral vector (pseudorabies) is subsequently triggered. In my effort to study the circuits engaged by DRG neurons, I've also participated in the generation of reporter mice (knock-ins, BAC transgenics, CRISPR) that allow a clearer picture of the distribution of subsets of primary afferent nociceptors and nociceptive projection neurons. I’ve also used transplantation of inhibitory precursor cells into the spinal cord to treat various models of chronic pain and chronic itch. I showed that these cells differentiate into GABAergic interneurons and integrate remarkably well into local spinal cord circuitry. I have also shown also that these cells are able to completely reverse the mechanical hypersensitivity that is produced by a peripheral nerve injury and significantly reduce spontaneous scratching and the severity of skin lesions in a model of chronic itch.
In collaboration with a graduate student in the lab, we molecularly profiled spinal cord projection neurons in order to better understand how different modalities of pain and itch are transmitted to the brain.
More recently, I started characterizing the distribution and expression of so-called "dark genes" (genes that are understudied in the "pain" field) in the DRG and spinal cord in order to identify novel targets for pain and itch. Among those genes, we are particularly interested in investigating the contribution of several ion channels in pain processing, namely Cacna2d1, 2d2, 2d3 and 2d4; Tmc3, 4, 5 and 7 as well as Qrfpr. For this, we characterize the behavioral consequences of knocking down the expression of each of these ion channels. I am also contributing to a project that focuses on developing new and promising pharmocological compounds for pain relief. This is a vast collaboration with both UCSF and non-UCSF laboratories that is funded by the Department of Defense. This project will provide several new drugs that inhibit known "pain receptors" and exhibit higher analgesic efficacy and lower side effects profiles than what is currently available. My role is to supervise the "in vivo" team that characterizes the analgesic properties of the compounds in rodents, in the setting of both acute and chronic pain. Among those targets, we are particularly interested in the alpha-2A adrenergic receptor, for which we have developed and characterized a novel agonist that exhibits strong analgesic anti-allodynic effects but is devoid of the sedative effects that characterize many of the alpha 2A drugs. Other targets that are under investigating include the receptors for sigma 2, cannabinoid 1, prostaglandin 1 and 4, serotonin transporter and mu opioid receptors. I have generated conditional knock-out mice for all these genes so that we can selectively knock down their expression in the DRG and spinal cord.