Areas of Interest

Research Interests

Nociceptor mechanisms and functions important for persistent pain

 

Nociceptors are primary sensory neurons specialized to detect injury and inflammation, and to trigger complex protective responses, including pain and anxiety. A major driver of chronic pain is persistent hyperexcitability and consequent “spontaneous” electrical activity in nociceptors. These long-lasting excitability alterations, along with associated synaptic alterations, provide a cellular memory of bodily injury. Our research combines novel hypotheses about nociceptor function with mechanistic investigations that are revealing overlooked molecular targets in nociceptors that may lead to new and improved treatments for chronic pain. A major focus is on complex excitability alterations that are retained in dissociated nociceptor cell bodies after induction in vivo by various pain-inducing conditions, including surgery, spinal cord injury, and chemotherapy (cisplatin treatment). Nociceptor hyperexcitability depends upon ongoing activity of multiple ion channels (including TRPV1 channels and several voltage-gated Na+ and Ca2+ channels), which depend in turn upon activity in several cell signaling pathways, including cAMP and ERK pathways. Our highly collaborative approach combines sophisticated behavioral, whole cell patch clamp, pharmacological, biochemical, and molecular methods. In addition, our comparisons of the functions and mechanisms of persistent nociceptor hyperexcitability across different pain and injury conditions in diverse species (humans, rats, mice, squid, snails) have provided insight into the evolution of core mechanisms that can promote chronic pain and associated alterations of behavior and mood.

Publications

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References

  • Tian, J, Bavencoffe, AG, Zhu, MX, Walters, ET. (2023). Readiness of nociceptor cell bodies to generate spontaneous activity results from background activity of diverse ion channels and high input resistance. Pain, DOI: 10.1097/j.pain.0000000000003091
  • Walters, ET, Crook, RJ, Neely, GG, Price, TJ, Smith, ESJ. (2023). Persistent nociceptor hyperactivity as a painful evolutionary adaptation. Trends Neurosci, 46:211–227.
  • Cuevas-Diaz Duran, R, Li, Y, Garza Carbajal, A, You, Y, Dessauer, CW, Wu, J, Walters, ET. (2023). Major Differences in Transcriptional Alterations in Dorsal Root Ganglia Between Spinal Cord Injury and Peripheral Neuropathic Pain Models. J Neurotrauma, 40:883–900.
  • Bavencoffe, AG, Spence, EA, Zhu, MY, Garza-Carbajal, A, Chu, KE, Bloom, OE, Dessauer, CW, Walters, ET. (2022). Macrophage Migration Inhibitory Factor (MIF) Makes Complex Contributions to Pain-Related Hyperactivity of Nociceptors after Spinal Cord Injury. J Neurosci, 42:5463–5480.
  • Lopez, ER, Carbajal, AG, Tian, JB, Bavencoffe, A, Zhu, MX, Dessauer, CW, Walters, ET. (2020). Serotonin enhances depolarizing spontaneous fluctuations, excitability, and ongoing activity in isolated rat DRG neurons via 5-HT4 receptors and cAMP-dependent mechanisms. Neuropharmacology, 184:108408.
  • Laumet, G, Bavencoffe, A, Edralin, JD, Huo, XJ, Walters, ET, Dantzer, R, Heijnen, CJ, Kavelaars, A. (2020). Interleukin-10 resolves pain hypersensitivity induced by cisplatin by reversing sensory neuron hyperexcitability. Pain, 161:2344–2352.
  • Berkey, SC, Herrera, JJ, Odem, MA, Rahman, S, Cheruvu, SS, Cheng, X, Walters, ET, Dessauer, CW, Bavencoffe, AG. (2020). EPAC1 and EPAC2 promote nociceptor hyperactivity associated with chronic pain after spinal cord injury. Neurobiol Pain, 7:100040.
  • Garza Carbajal, A, Bavencoffe, A, Walters, ET, Dessauer, CW. (2020). Depolarization-Dependent C-Raf Signaling Promotes Hyperexcitability and Reduces Opioid Sensitivity of Isolated Nociceptors after Spinal Cord Injury. J Neurosci, 40:6522–6535.
  • Odem, MA, Lacagnina, MJ, Katzen, SL, Li, J, Spence, EA, Grace, PM, Walters, ET. (2019). Sham surgeries for central and peripheral neural injuries persistently enhance pain-avoidance behavior as revealed by an operant conflict test. Pain, 160:2440–2455.
  • Mihail, SM, Wangzhou, A, Kunjilwar, KK, Moy, JK, Dussor, G, Walters, ET, Price, TJ. (2019). MNK-eIF4E signalling is a highly conserved mechanism for sensory neuron axonal plasticity: evidence from Aplysia californica. Philos Trans R Soc Lond B Biol Sci, 374:20190289.
  • Walters, ET. (2019). Adaptive mechanisms driving maladaptive pain: how chronic ongoing activity in primary nociceptors can enhance evolutionary fitness after severe injury. Philos Trans R Soc Lond B Biol Sci, 374:20190277.
  • Odem, MA, Bavencoffe, AG, Cassidy, RM, Lopez, ER, Tian, J, Dessauer, CW, Walters, ET. (2018). Isolated nociceptors reveal multiple specializations for generating irregular ongoing activity associated with ongoing pain. Pain, 159:2347–2362.
  • Walters, ET. (2018). Defining pain and painful sentience in animals. Animal Sentience,3. DOI: 10.51291/2377-7478.1360.
  • Bavencoffe, A, Li, Y, Wu, Z, Yang, Q, Herrera, J, Kennedy, EJ, Walters, ET, Dessauer, CW. (2016). Persistent electrical activity in primary nociceptors after spinal cord Injury is maintained by scaffolded adenylyl cyclase and protein kinase A and Is associated with altered adenylyl cyclase regulation. J Neurosci, 36:1660–1668.
  • Yang, Q, Wu, Z, Hadden, JK, Odem, MA, Zuo, Y, Crook, RJ, Frost, JA, Walters, ET. (2014). Persistent pain after spinal cord injury is maintained by primary afferent activity. J Neurosci, 34:10765–10769.
  • Crook, RJ, Dickson, K, Hanlon, RT, Walters, ET. (2014). Nociceptive sensitization reduces predation risk. Curr Biol, 24:1121–1125.
  • Wu, Z, 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. Pain, 154:2130–2141.
  • Crook, RJ, Hanlon, RT, Walters, ET. (2013). Squid have nociceptors that display widespread long-term sensitization and spontaneous activity after bodily injury. J Neurosci, 33:10021–10026.
  • 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. (1994). Injury-related behavior and neuronal plasticity: an evolutionary perspective on sensitization, hyperalgesia, and analgesia. Int Rev Neurobiol, 36:325–427.
  • Walters, ET, Alizadeh, H, Castro, GA. (1991). Similar neuronal alterations induced by axonal injury and learning in Aplysia. Science, 253:797–799.