Assistant Professor, SINTN, Departments of Anesthesia and (by courtesy) Molecular and Cellular Physiology (2012 - Present)
Honors & Awards
K99/R00 Pathway to Independence Award, NIH/NIDA (2011)
International Trainee Fellowship funded by the Scan|Design Foundation BY INGER & JENS BRUUN, International Association for the Study of Pain (2009)
Postdoc. (2), Columbia University, MacDermott Laboratory, Spinal Cord Physiology (2012)
Postdoc. (1), UCSF, Basbaum Laboratory, Neurobiology of Pain (2006)
Ph.D., Louis Pasteur University of Strasbourg, Cellular and Molecular Biology (2005)
Pharm.D., Louis Pasteur University of Strasbourg, Pharmacology (2001)
Current Research and Scholarly Interests
Cellular and Molecular Mechanisms of Pain and its Control by Opioids
Our laboratory searches to resolve the identity of the neurons in the nerves, spinal cord and brain that participate in generating the sensation of pain, and to uncover the molecular mechanisms that regulate neural activity in pain circuits.
Pain is normally an acute, physiological sensation that we experience when our body is exposed to noxious and potentially damaging stimuli (e.g. noxious heat of an open flame). The unpleasantness of pain drives us to engage adaptive behaviors for avoiding these stimuli and favoring healing. However, when chronic, pain is a disease that severely affects the quality of life of many patients. Injuries or diseases (trauma, diabetes, arthritis, cancer, etc) can induce neuroplasticity in somatosensory circuits that leads to miscoding of sensory information: pain can then become spontaneous and be perceived in the absence of actual stimuli, and normally innocuous stimuli such as light touch or warmth can generate excruciating pain.
We want to understand how neural circuits are functionally organized to encode qualitatively and quantitatively distinct pain signals, and to allow discrimination of pain from other somatosensory experiences such as touch or itch. Our ultimate goal is to identify the changes in this organization that underlie pathological chronic pain and to discover new molecular targets to treat this disease. One of our approaches is to gain understanding of how our endogenous opioid system functions. Opioid receptors and peptides composing this system modulate pain threshold and underlie the effect of the oldest, but still most effective, pain killers, namely opium poppy-extracted morphine and its derivatives. We search to establish the mechanisms by which opioids generate analgesia and detrimental side effects (e.g. tolerance, addiction, hyperalgesia, etc) to develop more efficient and safer analgesic treatments for managing pathological pain. To reach this goal we combine a variety of experimental approaches including molecular and cellular biology, neuroanatomy, electrophysiology, optogenetics and behavior.
In Vivo Visualization of Delta Opioid Receptors upon Physiological Activation Uncovers a Distinct Internalization Profile
JOURNAL OF NEUROSCIENCE
2012; 32 (21): 7301-7310
G-protein-coupled receptors (GPCRs) mediate numerous physiological functions and represent prime therapeutic targets. Receptor trafficking upon agonist stimulation is critical for GPCR function, but examining this process in vivo remains a true challenge. Using knock-in mice expressing functional fluorescent delta opioid receptors under the control of the endogenous promoter, we visualized in vivo internalization of this native GPCR upon physiological stimulation. We developed a paradigm in which animals were made dependent on morphine in a drug-paired context. When re-exposed to this context in a drug-free state, mice showed context-dependent withdrawal signs and activation of the hippocampus. Receptor internalization was transiently detected in a subset of CA1 neurons, uncovering regionally restricted opioid peptide release. Importantly, a pool of surface receptors always remained, which contrasts with the in vivo profile previously established for exogenous drug-induced internalization. Therefore, a distinct response is observed at the receptor level upon a physiological or pharmacological stimulation. Altogether, direct in vivo GPCR visualization enables mapping receptor stimulation promoted by a behavioral challenge and represents a powerful approach to study endogenous GPCR physiology.
View details for DOI 10.1523/JNEUROSCI.0185-12.2012
View details for Web of Science ID 000304421000022
View details for PubMedID 22623675
Behavioral indices of ongoing pain are largely unchanged in male mice with tissue or nerve injury-induced mechanical hypersensitivity
2011; 152 (5): 990-1000
Despite the impact of chronic pain on the quality of life in patients, including changes to affective state and daily life activities, rodent preclinical models rarely address this aspect of chronic pain. To better understand the behavioral consequences of the tissue and nerve injuries typically used to model neuropathic and inflammatory pain in mice, we measured home cage and affective state behaviors in animals with spared nerve injury, chronic constriction injury (CCI), or intraplantar complete Freund's adjuvant. Mechanical hypersensitivity is prominent in each of these conditions and persists for many weeks. Home cage behavior was continuously monitored for 16 days in a system that measures locomotion, feeding, and drinking, and allows for precise analysis of circadian patterns. When monitored after injury, animals with spared nerve injury and complete Freund's adjuvant behaved no differently from controls in any aspect of daily life. Animals with CCI were initially less active, but the difference between CCI and controls disappeared by 2 weeks after injury. Further, in all pain models, there was no change in any measure of affective state. We conclude that in these standard models of persistent pain, despite the development of prolonged hypersensitivity, the mice do not have significantly altered "quality of life." As alteration in daily life activities is the feature that is so disrupted in patients with chronic pain, our results suggest that the models used here do not fully reflect the human conditions and point to a need for development of a murine chronic pain model in which lifestyle changes are manifest.
View details for DOI 10.1016/j.pain.2010.12.003
View details for Web of Science ID 000289507500010
View details for PubMedID 21256675
VGLUT2 expression in primary afferent neurons is essential for normal acute pain and injury-induced heat hypersensitivity
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2010; 107 (51): 22296-22301
Dorsal root ganglia (DRG) neurons, including the nociceptors that detect painful thermal, mechanical, and chemical stimuli, transmit information to spinal cord neurons via glutamatergic and peptidergic neurotransmitters. However, the specific contribution of glutamate to pain generated by distinct sensory modalities or injuries is not known. Here we generated mice in which the vesicular glutamate transporter 2 (VGLUT2) is ablated selectively from DRG neurons. We report that conditional knockout (cKO) of the Slc17a6 gene encoding VGLUT2 from the great majority of nociceptors profoundly decreased VGLUT2 mRNA and protein in these neurons, and reduced firing of lamina I spinal cord neurons in response to noxious heat and mechanical stimulation. In behavioral assays, cKO mice showed decreased responsiveness to acute noxious heat, mechanical, and chemical (capsaicin) stimuli, but responded normally to cold stimulation and in the formalin test. Strikingly, although tissue injury-induced heat hyperalgesia was lost in the cKO mice, mechanical hypersensitivity developed normally. In a model of nerve injury-induced neuropathic pain, the magnitude of heat hypersensitivity was diminished in cKO mice, but both the mechanical allodynia and the microgliosis generated by nerve injury were intact. These findings suggest that VGLUT2 expression in nociceptors is essential for normal perception of acute pain and heat hyperalgesia, and that heat and mechanical hypersensitivity induced by peripheral injury rely on distinct (VGLUT2 dependent and VGLUT2 independent, respectively) primary afferent mechanisms and pathways.
View details for DOI 10.1073/pnas.1013413108
View details for Web of Science ID 000285521800066
View details for PubMedID 21135246
Cellular and Molecular Mechanisms of Pain
2009; 139 (2): 267-284
The nervous system detects and interprets a wide range of thermal and mechanical stimuli, as well as environmental and endogenous chemical irritants. When intense, these stimuli generate acute pain, and in the setting of persistent injury, both peripheral and central nervous system components of the pain transmission pathway exhibit tremendous plasticity, enhancing pain signals and producing hypersensitivity. When plasticity facilitates protective reflexes, it can be beneficial, but when the changes persist, a chronic pain condition may result. Genetic, electrophysiological, and pharmacological studies are elucidating the molecular mechanisms that underlie detection, coding, and modulation of noxious stimuli that generate pain.
View details for DOI 10.1016/j.cell.2009.09.028
View details for Web of Science ID 000270857500012
View details for PubMedID 19837031
Dissociation of the Opioid Receptor Mechanisms that Control Mechanical and Heat Pain
2009; 137 (6): 1148-1159
Delta and mu opioid receptors (DORs and MORs) are inhibitory G protein-coupled receptors that reportedly cooperatively regulate the transmission of pain messages by substance P and TRPV1-expressing pain fibers. Using a DOReGFP reporter mouse we now show that the DOR and MOR are, in fact, expressed by different subsets of primary afferents. The MOR is expressed in peptidergic pain fibers, the DOR in myelinated and nonpeptidergic afferents. Contrary to the prevailing view, we demonstrate that the DOR is trafficked to the cell surface under resting conditions, independently of substance P, and internalized following activation by DOR agonists. Finally, we show that the segregated DOR and MOR distribution is paralleled by a remarkably selective functional contribution of the two receptors to the control of mechanical and heat pain, respectively. These results demonstrate that behaviorally relevant pain modalities can be selectively regulated through the targeting of distinct subsets of primary afferent pain fibers.
View details for DOI 10.1016/j.cell.2009.04.019
View details for Web of Science ID 000266916400025
View details for PubMedID 19524516
Knockin mice expressing fluorescent delta-opioid receptors uncover G protein-coupled receptor dynamics in vivo
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2006; 103 (25): 9691-9696
The combination of fluorescent genetically encoded proteins with mouse engineering provides a fascinating means to study dynamic biological processes in mammals. At present, green fluorescent protein (GFP) mice were mainly developed to study gene expression patterns or cell morphology and migration. Here we used enhanced GFP (EGFP) to achieve functional imaging of a G protein-coupled receptor (GPCR) in vivo. We created mice where the delta-opioid receptor (DOR) is replaced by an active DOR-EGFP fusion. Confocal imaging revealed detailed receptor neuroanatomy throughout the nervous system of knock-in mice. Real-time imaging in primary neurons allowed dynamic visualization of drug-induced receptor trafficking. In DOR-EGFP animals, drug treatment triggered receptor endocytosis that correlated with the behavioral response. Mice with internalized receptors were insensitive to subsequent agonist administration, providing evidence that receptor sequestration limits drug efficacy in vivo. Direct receptor visualization in mice is a unique approach to receptor biology and drug design.
View details for DOI 10.1073/pnas.0603359103
View details for Web of Science ID 000238660400055
View details for PubMedID 16766653