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| University of Toronto | UTCSP | Physiology Department | Molecular Pain |
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Pain, Emotion, and FearSummaryNeurons and synapses in the central nervous systems are plastic, and can undergo long-term changes throughout life. Studies of molecular and cellular mechanisms of such changes not only provide important insight into how we learn and store new knowledge in our brains, but also reveal the mechanisms of pathological changes occurring following an injury such as chronic pain and fear memory. Integrative experimental approachesWe investigate the molecular and cellular mechanisms of synaptic transmission and plasticity in the central nervous system and functional implications of such plastic changes. The laboratory employs integrative approaches, a combination of genetic, electrophysiological, pharmacological and behavioral methods, to study physiological and pathological mechanisms for pain and emotional fear. At the single neuron level, whole-cell patch clamp recordings of synaptic responses are made from single neurons in brain and spinal cord slices. At the system level, neuronal evoked responses in intact or freely moving animals are performed to study neuronal plasticity in emotional learning, persistent pain and anxiety. At the behavioral level, a combination of pharmacological and genetic approaches in mice (genetic mutant mice) allows us to study molecular mechanisms of behaviors. Pain: physiological pain is important for the survivalPain is the unpleasant experience or sensation induced by noxious stimuli. Nociceptive information enters the brain through spinal-brain projecting systems, and projecting to widely different brain areas. Most of all, painful inputs enter the forebrain areas including the anterior cingulate cortex (ACC) and insular cortex, and trigger unpleasant sensation or experience. Painful inputs projected into the somatosensory cortex help to determine the location and quality of painful stimuli. Hippocampus, a structure known to be important for spatial memory, is also activated by painful stimuli, and may contribute to the formation of pain-related spatial memory. Neuronal inputs into the amygdala and its related structures play important roles in forming fear memory and pain-emotional responses. Furthermore, nociceptive inputs also activate endogenous analgesia systems including neurons in the periaqueductal gray (PAG) and brainstem rostral ventromedial medulla (RVM). Activation of endogenous analgesia systems excite descending inhibitory systems and modulate sensory transmission at the level of spinal cord as well as possible supraspinal structures. Through activating descending inhibitory systems, painful information entering the central nervous system is significantly reduced. Thus, acute pain or physiological pain is physiologically important for survival, and bearable, and does not get transferred into chronic pain or pathological pain. Chronic pain: is unnecessary, and caused human sufferingMany studies of plastic changes related to pathological pain are mainly focused in the dorsal root ganglion (DRG) and spinal cord dorsal horn. However, recent studies demonstrate that central plasticity happen within the ACC after injury. There are three major reasons why the study of central cortical plasticity is important for pathological pain. First, pain or pain-related unpleasantness are encoded in the forebrain areas such as the ACC; Second, higher brain structures play important roles in many mental dysfunction related to chronic pain and long-term use of pain medicines. Finally, central activity itself may produce pain sensation and play important roles in spontaneous pain or central pain. Unlike acute pain or physiological pain, chronic pain is pathological, and does not offer obvious health benefits. Synaptic plasticity: pain, memory and fearWe propose that while neuronal mechanisms underlying physiological functions such as learning and memory may share some common signaling molecules with abnormal or injury-related changes in the brain during the induction, distinct synaptic and neuronal network mechanisms are involved in pathological pain and fear as compared with that of cognitive learning and memory. Among several key-signaling molecules involved in the central plasticity, we focus on calcium- and calcium-calmodulin related pathways for basic and translational neuroscience researches. Spinal silent synapses and long-term facilitationNeurons in spinal cord dorsal horn serve as the first relays for peripheral sensory inputs entering the brain. Understanding mechanisms for sensory synaptic transmission, regulation and plasticity in spinal dorsal horn provide the basic information about central processing of incoming information. Using whole-cell patch-clamp recording techniques in spinal slices, we demonstrated that glutamate is the only fast excitatory neurotransmitter in the lumbar dorsal horn sensory synapses. Some of sensory synapses in the spinal cord are ‘silent’. The recruitment of silent synapses by neurotransmitter serotonin (5-HT) provides a novel synaptic mechanism for the enhancement of sensory transmission, requiring the interaction between AMPA receptor and PDZ proteins. Long-term facilitatory effects of 5-HT in spinal dorsal horn neurons are developmentally regulated by cAMP-related signaling pathways. Kainate receptor as a pain target: transmission/modulationPostsynaptic sensory responses induced at noxious intensities were mediated by both glutamate AMPA and kainate receptors, while non-noxious sensory responses were almost mediated by AMPA receptors. Activation of kainate receptors, depending on subtypes of receptors, also modulates spinal inhibitory transmission. Forebrains: NO brain no painGenetic studies from ‘smart mice’ suggest that neurons in the forebrain structures including the ACC play important roles in injury-related plastic changes and fear-induced memory. Using complementary approaches, we found that immediate early genes such as Egr-1 and pCREB are activated in after the injury or fearful shocks. In parallel with these mapping, electrophysiological recordings are performed from brain slices prepared from various brain areas including the brainstem, amygdala, hippocampus, ACC, insular cortex, somatosensory cortex, auditory cortex and visual cortex. Synaptic responses and synaptic plasticity (LTP and LTD) are examined. Using conditioning transgenic and gene knockout mice, we are able to correlate the results of cellular studies with whole animal behaviors. An example of the strength of this integrative approach is the studies of mice that overexpress the NR2B receptor selectively in the forebrain including the ACC. We show that alterations in both behavioral (learning and memory) and cellular correlates (LTP) of the memory formation process. Furthermore, the same mice showed selectively enhanced persistent pain without any change in acute pain, suggesting in the first time that forebrain NMDA receptors play important roles in persistent pain. Pain facilitatory systemsBiphasic modulation of spinal nociceptive transmission from the RVM, perhaps reflecting the different types of neurons identified in this area, offer fine regulation of spinal sensory thresholds and responses. While descending inhibition is primarily involved in regulating suprathreshold responses to noxious stimuli, descending facilitation reduces the neuronal threshold to nociceptive stimulation. Descending facilitation has a general impact on spinal sensory transmission, inducing sensory inputs from cutaneous and visceral organs. Descending facilitation can be activated under physiological conditions, and one physiological function of descending facilitation is to enhance animals’ ability to detect potential dangerous signals in the environment. Indeed, neurons in the RVM not only respond to noxious stimuli, but also show ‘learning’-type changes during repetitive noxious stimuli. More importantly, RVM neurons can undergo plastic changes during and after tissue injury and inflammation. Descending facilitation is likely activated after the injury, contributing to secondary hyperalgesia. Blocking descending facilitation, by lesion of the RVM or spinal blockade of 5-HT receptors, is antinociceptive. The descending facilitatory system therefore serves as a double-edged blade in the central nervous system. On one hand, it allows neurons in different parts of the brain to communicate with each other and enhance sensitivity to potentially dangerous signals; on the other hand, prolonged facilitation of spinal nociceptive transmission after injury speeds up central plastic changes related to chronic pain. Clinical implicationsPathological pain is likely a result of long-term plastic changes along somatosensory pathways, from the periphery to cortex. Due to long-term plastic changes in central regions, pain specificity is lost in the somatosensory pathway, at least from areas where allodynia was reported. Thus, drugs developed based on physiological pain mechanism may not be used for treating pathological pain. Understanding pathological pain requires understanding of plastic changes in somatosensory pathways, mainly the central nervous systems. ReferencesZhuo M, Small SA, Kandel ER, Hawkins RD (1993). Science, 260:1946-1950. Zhuo M, Hu Y, Schultz C, Kandel ER, Hawkins RD (1994). Nature, 368:635-639. Zhuo M, Gebhart GF (1992). Journal of Neurophysiology, 67:1599-1614. Li, P, Zhuo, M (1998). Nature, 393:695-698. Li, P, Wilding, TJ, Kim, SJ, Calejesan, AA, Huettner, JE, Zhuo, M (1999). Nature, 1999, 397:161-164. Tang, YP, Shimizu, E., Dube, G., Rampon, C., Kerchner, G.A., Zhuo, M., Liu, G. and Tsien, J.Z (1999). Nature, 401:63-69. Li, P, Kerchner, G.A., Sala, C., Wei, F., Huettner, JE, Sheng, M. and Zhuo, M (1999). Nature Neuroscience, 1999, 2:972-977. Wei, F., Li, P. and Zhuo, M (1999). Journal of Neuroscience, 19:9346-9354. Wei, F., Wang, G.-D., Kerchner, G.A., Kim, S.J., Xu, H.-M., Chen, Z.-F. and Zhuo, M (2001). Nature Neuroscience, 4:164-169. Kerchner, G.A., Wang, G.D. and Qiu, C.-S., Huettner, J.E. and Zhuo, M (2001). Neuron, 32:477-488. Wei F, Qiu CS, Liauw J, Robinson DA, Ho N, Chatila T, Zhuo M (2002). Nature Neuroscience, 5:573-579. Zhuo, M (2002). Drug Discov Today. 7:259-267 Wei F, Qiu CS, Kim SJ, Muglia L, Maas JW, Pineda VV, Xu HM, Chen ZF, Storm DR, Muglia LJ, Zhuo M. (2002). Neuron, 36:713-726. Zhuo, M (2004). Novaris Foundation symposium, Pathological pain: from molecular to clinical aspects. Wiley, Chichester, Page 132-148. Zhao MG, Toyoda H, Lee Y.-S., We LJ, Ko SW, Zhang XH, Jia Y.H., Shum F, Xu H, Li B-M, Kaang B.-K. and Zhuo M. (2005) Neuron, 47:1-14. News articles for general public readers:1998 Bioworld Today: June 22, 1998. From injury to ouch, neuronal pathway research turns up “silent” new analgesic concept. The Scientist_The Notebook, PAIN EXPLAINED: Washington University's Min Zhuo found that a region of the brain in rats could activate neurons in the spinal cord, possibly causing feelings ... www.the-scientist.com/yr1998/july/notebook_980706.html. 1999 NIH, NIDA: “Normally Silent Synapses in Spinal Cord Become Active to Produce Chronic Pain” National Institute on Drug Abuse, Director's Report to the National Advisory Council on Drug Abuse; February, 1999. 2001 Science, news room, January 26, 2001, “No pain, no brains?” www.academicpress.com/inscight/01292001 Lancet, February 3, 2001. Memory gain means more pain for transgenic mice. “Can Smart Be Painful? “ At least in mice, the two seem somehow linked; http://www.healingwell.com/ New Scientist: March 2, 2002, Painful memories: Bad Memories www.newscientist.com NR2B Protein May Be An Attractive Target For The Treatment Of Chronic Pain. www.hum-molgen.de/NewsGen/02-2001/msg20.html 2002 2003 The Scientist “Gains in Pain Research”. December 15, 2003. The Lancet Neurology “Taking a shot at neuropathic pain” Vol. 2, December, Page 719. 2005 Toronto Star front page story: “Scared? It is all in your anterior cingulate cortex” Globe TV: Night scientific news; September 16, 2005 Medical News Today: How and where a painful event becomes permanently etched in the brain United Press Internationa;
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