In Memoriam of Dr. Ke-Fei Shen; died November 17, 2012
(by Dr. Stanley M. Crain, Professor Emeritus, Albert Einstein College of Medicine)
I met Ke-Fei in 1980 at the “Shanghai Workshop on Neurobiology”, an historic conference at the Brain Research Institute in Shanghai. The Chinese National Academy of Sciences had invited me, along with a dozen U.S. and European neuroscientists, in order to update 100 young Chinese neuroscientists (including Dr. Shen) on recent trends in Western neuroscience research. This conference was co-sponsored by the U.S. National Academy of Sciences and provided the first official contact between U.S. and Chinese neuroscientists after many years of intellectual isolation during the brutal Chinese “cultural revolution!”
I was about 57 years old during my visit to Shanghai and among the bright young Chinese neuroscientists at the conference was Dr. Ke-Fei Shen, who was then 48 and already established as a prominent leader of the Shanghai Brain Research Institute. He was evidently inspired by my lecture about utilizing electrophysiologic analyses of nerve tissue cultures to analyze the mechanisms of action of opioids. In collaboration with Dr. Eric Simon (co-discoverer of opioid receptors), we had recently demonstrated that sensory-evoked dorsal-horn synaptic networks discharges in organotypic tissue cultures of mouse spinal cord with attached dorsal root ganglia were selectively depressed by perfusion with a series of exogenous and endogenous opioids, at concentrations remarkably proportionate to their potency in the intact animal (Crain et al, Brain Research, 1978).
Several years later, I received a letter from the director of the Shanghai Brain Research Institute indicating that Dr. Shen would like to visit my laboratory at the Albert Einstein College of Medicine en route from a 6-month visiting research scholarship in France. Dr. Shen arrived in my lab around 1985 and he was so impressed with our opioid research projects that he decided to prolong his visit for “a while”. Ke-Fei and I interacted so well together that he finally made a crucial decision to join my laboratory and cancel his prior commitment to return to the Shanghai Brain Research Institute!
Dr. Shen skillfully initiated a series of elegant electrophysiologic analyses of opioid effects on dorsal-root ganglion neurons in our organotypic cord-ganglion tissue cultures, utilizing intracellular microelectrode techniques that I had developed many years earlier (Crain, Journal of Comparative Neurology, 1956). Within a year we were able to obtain significant experimental evidence that opioids could evoke not only well-known inhibitory signaling effects but also novel excitatory signaling in action potential of the same sensory neuron. These excitatory effects were shown to be selectively elicited by >1,000-fold lower opioid concentrations than required to elicit inhibitory effects. Excitatory opioid effects were selectively enhanced by application of pharmacologic agents that increase the cyclic AMP levels in these neurons (Shen & Crain, Brain Research, 1989). This seminal paper stimulated a remarkable series of pharmacologic and biochemical studies initially aimed at molecular mechanisms underlying these novel opioid-evoked excitatory effects in sensory neurons and subsequently applied to broader problems, e.g. opioid-induced hyperalgesia, tolerance and dependence (published in Brain Research, PNAS, Pain and other prominent journals). After a decade of microelectorode analyses of opioid effects on sensory neurons in vitro, Dr. Shen and I began in 1995 another decade of significant pharmacologic behavioral studies of analgesia and hyperalgesia in mice, utilizing antinociception and hyperalgesia hot-water tail-flick assays. These studies led to our discovery of novel methods to attenuate tolerance and dependence during chronic opioid treatment of mice as well as pain patients by co-treatment with ultra-low-dose naltrexone or neuraminidase inhibitors of GMI ganglioside.
Finally, we demonstrated that a significant degree of opioid-like analgesia could be elicited in mice without the use of exogenous opioids. Naïve mice were injected with cyclic AMP-phosphodiesterase inhibitors, e.g., rolipram or caffeine, resulting in hyperalgesia and the release of endogenous opioids, i.e., endorphins. Subsequent injection of ultra-low-dose naltrexone resulted in the rapid onset of opioid-mediated (naltrexone-reversible) analgesia (Crain & Shen, Brain Research, 2008).
Dr. Shen and I were, indeed, delighted to have had the opportunity to demonstrate this animal model of endorphinergic analgesia as the culmination of our research projects at the Albert Einstein College of Medicine! This study also provided the pharmacologic rationale for development of novel clinical treatments of severe emotional and physical distress dysfunction disorders, including chronic anxiety, addiction, and pain, in collaboration with my son , Dr. Steven Crain, a clinical psychologist. Successful pilot studies have recently been carried out with a dietary endorphinergic formulation (Endorphinate®) developed by Pondera Pharmaceuticals Inc.
Dr. Shen’s pioneering intracellular microelectrode analyses of the bimodal excitatory/inhibitory functions of opioid receptors in sensory neurons in tissue culture have, indeed, provided remarkably fruitful insights into complex behavioral activities of the entire nervous system, far beyond our wildest expectations when we started this collaborative project in the 1980’s!
— by Dr. Stanley M. Crain, Professor Emeritus, Albert Einstein College of Medicine