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Researchers
  • Dr.  Alexander Binshtok
Dr Alexander Binshtok
 
CV
 
Degree: 2006 - PhD summa cum laude from Hebrew University
 
Post-doc: 2006-2007 – Neural Plasticity Research Group – Harvard Medical School & Massachusetts General Hospital (Dr. Clifford Woolf) 
 
Other Academic positions: 2007-2010 – Faculty (Instructor in Anesthesia) Harvard Medical School
 
Position in Hebrew University:
 
2010 – Senior Lecturer
 
2017 - Chair, Jacob and Lena Joels Memorial Foundation for Excellence in the Life and Medical Sciences
 
 
Research Interests
 
Pain is a major unmet medical need that has reached pandemic scale, causing extensive personal suffering and costing hundreds of billions of dollars every year in medical expenses and lost productivity. Lack of adequate understanding of the mechanisms of pain prevents the development of more effective therapies. Although it is essentially a sensation, pain has strong cognitive and emotional components that all together make pain thrilling multidimensional physiological phenomenon. As such, comprehension of pain mechanisms, in addition to obvious clinical implications, provides a unique window of insight into complex functions of the peripheral and central nervous system.
 
Rephrasing the famous Sun Tzu’s Art of War saying "know your enemy" - biological organisms must know about danger in order to deal with it efficiently. This is what nociceptors do: these primary sensory neurons are specialized to detect intense stimuli using a repertoire of specific high threshold heat-, mechanical- or chemical-sensitive ion channels. Activation of these channels produces inward currents that create generator potentials. These potentials activate voltage-gated sodium currents that, after an activation threshold is exceeded, lead to a flow of action potentials from the periphery to the central nervous system thereby signaling the presence, location and intensity of noxious stimuli. Since the first description of peripheral pain sensation (nociception) by Charles Sherrington about 100 years ago substantial progress has been made in understanding the particular functions of nociceptive neurons. Nevertheless, exactly how nociceptive terminals transduce and transmit noxious stimuli, how this information is analyzed and memorized by the central nervous system and how these afferent signals are modulated by tissue injury or inflammation remains unclear.
 
Our lab studies “behavior” of living pain-specific neuronal cells in cultures and brain slices. We record electrical activity of neuronal cells and pain fibers using patch clamp and ion imaging techniques.
 
In-Vitro physiology set up 
 Figure 1. In-vitro physiology setup
 
We also use advanced tests to characterize in-vivo behavioral responses to various noxious stimuli.
 
By using these techniques we are able to assess properties of ion channels and signaling pathways that underlie detection, transmission and perpetuation of pain signals. We study how activation and modulation of pain specific transducer channels and voltage-gated ion channels leads to the perception of noxious stimuli in normal and pathological conditions. Detailed understanding of the complex mechanisms that underlie pain are providing essential knowledge paramount in the development of novel effective therapies. During my postdoctoral fellowship my mentors Dr. Clifford Woolf and Dr. Bruce Bean and I demonstrated that charged membrane impermeable sodium-channel blockers can be targeted selectively into peripheral pain-sensing neurons (nociceptors) through TRP channels to produce pain-specific local anesthesia (Binshtok et al., Nature 2007). Under normal physiological conditions, membrane impermeable sodium-channel blockers, like QX-314, are inoperant because they cannot act upon the intracellular domain of sodium channels. Using capsaicin (the hot ingredient of chili) to activate the TRPV1 channel, the noxious thermo-sensitive transducer localized on high threshold nociceptors, we were able to introduce QX-314 into nociceptors, and thereby selectively block their electrical activity. Neurons that do not express TRPV1 were not blocked by the combination of QX-314 and capsaicin. Injection of QX-314 and capsaicin in vivo together but not alone abolished the response to noxious mechanical and thermal stimuli without any motor or tactile deficit.
 
This approach could be used clinically to produce long lasting regional analgesia while preserving motor and autonomic function. In addition to the application of this technology for surgery and childbirth, this technique could also be used to diminish postoperative and cancer pain, as well as inflammatory and neuropathic pain.
 
Figure 2 Coapplication of extracellular QX-314 and capsaicin selectively blocks sodium currents and prevents generation of action potential in small (soma diameter < 25 mm) capsaicin-responsive DRG neurons, but not in  large (soma diameter > 40 mm) capsaicin insensitive neurons.
 
 
 
 
 
 
 
 
 
 
 
Figure 2. Co-application of extracellular QX-314 and capsaicin selectively blocks sodium currents and prevents generation of action potential in small (soma diameter < 25 mm) capsaicin-responsive DRG neurons, but not in large (soma diameter > 40 mm) capsaicin insensitive neurons.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
To further understand mechanisms of inflammatory and neuropathic pain we assess intrinsic electrical and synaptic properties of pain neurons in models of chronic pain.  By utilizing various in-vitro, in-vivo, and ex-vivo models, we explore how different mediators that released following tissue injury and inflammation modify pain processing in attempt to determine the targets of these mediators and to study what are the mechanisms and signaling pathways that lead to changes in pain processing.
The results of our work will yield novel and fundamental insights into the molecular mechanisms of pain sensation and may elucidate new potential targets for the treatment of inflammatory and neuropathic pain and the development of new pain-specific anesthetic drugs.
 
 
 
 
Current Research Projects
 
Processing of nociceptive information at nerve terminals. Role of various receptors and ion channels in translation and transmission of noxious stimulus.
Effect of cytokines on kinetics of sodium channels and therefore on neuronal excitability and inflammatory pain.
Role and relative contribution of nociceptive and non-nociceptive fibers in pain that follows nerve injury (neuropathic) pain.
 
 
Targeted delivery of impermeant hydrophilic cationic inhibitors of intracellular enzymes through TRP or other large non-selective channels to modulate intracellular signal transduction and metabolism pathways in cancer cells, pain-and itch sensing neurons, and other cells while minimizing effects on other types of cells.
Cortical models of pain perception and pain-mediated plasticity
 
 
 
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