埃德加T. Walters, Ph.D.

Research Information

Nociceptor memory and chronic pain

Nociceptors are primary sensory neurons that detect injury and inflammation. Repeated or severe injury and inflammation can produce chronic, even life-long, pain. A major driver of several forms of chronic pain is persistent hyperexcitability and spontaneous electrical activity of nociceptors. These lasting alterations represent a cellular memory of bodily injury that is likely to involve mechanisms that are also used in the brain to store more conventional memories. Our goals are to define the mechanisms that cause nociceptors to become persistently hyperexcitable, to assess the functional consequences of this hyperexcitability, and to find new molecular targets within nociceptors offering promise for the treatment of chronic pain. These goals are pursued by two complementary approaches.

Nociceptor mechanisms driving chronic pain after spinal cord injury.The often permanent pain caused by spinal cord injury (SCI) is one of the most intractable forms of chronic pain known. We have found that behavioral hypersensitivity in rats tested months after SCI is closely correlated with a dramatic, widespread increase in the incidence of spontaneous activity (SA) in the cell bodies of nociceptors, with this SA being expressed both in vivo and for at least a day after dissociating and culturing nociceptors. Current projects employ multidisciplinary methods (behavioral tests, whole cell patch clamp, immunocytochemistry, biochemistry, molecular biology) to define electrophysiological mechanisms of SCI-induced SA, cell signaling alterations underlying the development and maintenance of chronic SA, and behavioral consequences of nociceptor SA.

Comparative insights into nociceptor memory functions and mechanisms.Our work and others’ have revealed striking similarities in how the nociceptors of invertebrates and vertebrates detect and “remember” injury-related stimulation. Mollusks offer well-known advantages for relating the properties of identifiable cells to behavioral functions. We use the large marine snail, Aplysia, to define cellular signaling pathways important for the induction and long-term maintenance of hyperexcitability in the cell body, axon, and peripheral and central terminals of identified nociceptors. Some of these signals also contribute to long-term alterations in vertebrate nociceptors, including the cAMP-PKA-CREB and NO-cGMP-PKG pathways. Others have not yet been investigated in vertebrates, such as a potent pathway that depends upon local depolarization (and protein synthesis) but not calcium signals. We found recently that another mollusc, the longfin Atlantic squid, displays long-term nociceptive sensitization of defensive behavior paralleled by sensitization of the peripheral branches of nociceptors. Comparisons of behavioral alterations and nociceptor memory in squid, Aplysia, and rats point to shared functions that have shaped the evolution of nociceptor plasticity and to conserved mechanisms that may be fundamental to many memory-like phenomena, including some forms of chronic pain.

Publications

Publication Information

References

• Crook RJ, Dickson K, Hanlon RT,Walters ET。(2014). Nociceptive sensitization reduces predation risk.Curr Biol., 24:1121–1125.
• Crook RJ,Walters ET。(2014). Neuroethology: self-recognition helps octopuses avoid entanglement.Curr Biol., 24:R520–1.
• Luo J,Walters ET,Carlton SM, and Hu H. (2013). Targeting Pain-evoking Transient Receptor Potential Channels for the Treatment of Pain.Curr Neuropharm., 11 (6):652 – 663.
• Wu ZZ, Yang Q, Crook RJ, O’Neil RG,Walters ET.(2013). TRPV1 channels make major contributions to behavioral hypersensitivity and spontaneous activity in nociceptors after spinal cord injury.J Pain., Oct; 154 (10): 2130-41.
• Yang Q, Wu ZZ, Crook RJ, Du J, Carlton SM,Walters ET。(2013). Opening of KCNQ/Kv7 channels blocks both spontaneous activity in small DRG neurons and signs of chronic pain after spinal cord injury.J Pain., 14, S54.
• Yin S*, Luo J*, Qian A, Du J, Yang Q, Zhou S, Yu W, Du G, Clark RB,Walters ET, Carlton SM, Hu H. (2013). Retinoids activate the irritant receptor TRPV1 and produce sensory hypersensitivity.J Clin Invest123(9):3941-51.
• Bedi SS, Lago MT, Masha LI, Crook RJ, Grill, RJ,Walters ET。(2012). Spinal cord injury triggers an intrinsic growth-promoting state in nociceptors.J Neurotrauma, 29:925–935.
• Walters ET。(2012). Nociceptors as chronic drivers of pain and hyperreflexia after spinal cord injury: an adaptive-maladaptive hyperfunctional state hypothesis.Front Physiol, 3:309 (open-access Article 309, 13 pages).
• Crook RJ, Lewis T, Hanlon RT,Walters ET。(2011). Peripheral injury induces long-term sensitization of defensive responses to visual and tactile stimuli in the squid Loligo pealeii, Lesueur 1821.J Exp Biol, 214:3173–3185.
• Crook RJ,Walters ET。(2011). Nociceptive behavior and physiology of molluscs: animal welfare implications.ILAR J, 52:185–195.
• Jin M, Wu Z, Chen L, James J, Collins D,Walters ET, and O’Neil RG. (2011). Determinants of TRPV4 activity following selective activation by small molecule agonist GSK1016790A.PLoS ONE, 6(2):e16713.
• Bedi S, Yang Q, Crook R, Du J, Wu Z, Fishman H, Grill R, Carlton S andWalters ET。(2010)。Chronic spontaneous activity generated in the somata of small dorsal root ganglion neurons is associated with pain-related behavior following spinal cord injury.J Neurosci30,14870-82.
• Kunjilwar KK, Fishman HM, Englot DJ, O’Neil RG, andWalters ET。(2010)。持久的兴奋过度诱导by depolarization in the absence of detectable Ca2+ signals.J Neurophysiol101, 1351-1360.
• Reyes FD andWalters ET。(2010)。Long-lasting synaptic potentiation induced by depolarization under conditions that eliminate detectable Ca2+ signals.J Neurophysiol103,1283-1294.
• Toy EC, Weisbrodt N, Dubinsky WP, O’Neil RG,Walters ET, Harms KP.Case Files: Physiology, 2nd edition。Lange Medical Books/McGraw-Hill, New York, (2009).
• Walters ET, Moroz LL. (2009). Molluscan memory of injury: Evolutionary insights into chronic pain and neurological disorders.Brain Behav Evol, 74206 - 218。
• Walters ET。(2009). Chronic pain, memory, and injury: Evolutionary clues from snail and rat nociceptors.Int J Comp Psychol, 22,127–140.
• Kunjilwar KK, Fishman HM, Englot DJ, O’Neil RG,Walters ET。(2009). Long-lasting hyperexcitability induced by depolarization in the absence of detectable Ca2+ signals,J Neurophysiol, 101,1351–1360.
• Weragoda RMS,Walters ET。(2007). Serotonin induces memory-like, rapamycin-sensitive hyperexcitability in sensory axons of Aplysia that contributes to injury responses.J Neurophysiol, 98:1231-1239.
• Song XJ, Wang ZB, Gan Q,Walters ET。(2006). cAMP and cGMP contribute to sensory neuron hyperexcitability and hyperalgesia in rats with dorsal root ganglia compression.J Neurophysiol, 95:479-492.
• Zheng JH,Walters ET, Song XJ. (2006). Dissociation of dorsal root ganglion neurons induces hyperexcitability that is maintained by increased responsiveness to cAMP and cGMP.J Neurophysiol, 97:15-25.
• Gasull X, Liao X, Dulin MF, Phelps C,Walters ET。(2005). Evidence that long-term hyperexcitability of the sensory neuron soma induced by nerve injury is adaptive.J Neurophysiol3:2218-2230.