Resilience to Stress and Resilience to Pain: Lessons from Molecular Neurobiology and Genetics

Chronic pain and behavioral stress represent major unmet medical needs. Some individuals are relatively resilient to pain or to behavioral stress. In some especially well-studied humans, it has been possible to identify particular neuronal cell types in the PNS and pinpoint particular genes that are major contributors to pain resilience. Recent research is beginning to illuminate the more complex factors that operate within the CNS to confer resilience to behavioral stress and pain. Improved understanding of resilience to pain and behavioral stress is likely to inform the development of novel treatments that would remain unknown by a sole focus on disease susceptibility. What biological factors account for resilience to pain or to behavioral stress? Here, we discuss examples of cellular and molecular mechanisms within disparate parts of the nervous system as contributors to such resilience. In some especially well-studied humans, it is possible to identify particular neuronal cell types in the peripheral nervous system (PNS) and pinpoint specific genes that are major contributors to pain resilience. We also discuss more complex factors that operate within the central nervous system (CNS) to confer resilience to behavioral stress. We propose that genetic and neurobiological substrates for resilience are discoverable and suggest more generally that neurology and psychiatry hold lessons for each other as investigators search for actionable, biological underpinnings of disease. What biological factors account for resilience to pain or to behavioral stress? Here, we discuss examples of cellular and molecular mechanisms within disparate parts of the nervous system as contributors to such resilience. In some especially well-studied humans, it is possible to identify particular neuronal cell types in the peripheral nervous system (PNS) and pinpoint specific genes that are major contributors to pain resilience. We also discuss more complex factors that operate within the central nervous system (CNS) to confer resilience to behavioral stress. We propose that genetic and neurobiological substrates for resilience are discoverable and suggest more generally that neurology and psychiatry hold lessons for each other as investigators search for actionable, biological underpinnings of disease. reduced interest in pleasurable stimuli, such as food, drink, sex, and exercise. an experimental model where a test C57BL/6J mouse is placed into the home cage of a larger, more aggressive CD1 mouse [35.Berton O. et al.Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress.Science. 2006; 311: 864-868Crossref PubMed Scopus (1608) Google Scholar]. Fighting ensues quickly but is restricted to 5–10 min to limit physical injury, after which time the two mice are separated by a divider, which prevents further physical contact but allows the aggressive cues of the larger mouse to be perceived. Over 10 days, the test mouse is exposed to a different aggressive mouse each day. CSDS induces similar rates of susceptibility and resilience in male and female C57BL/6J mice, although different experimental procedures are used for the two sexes [38.Harris A.Z. et al.A novel method for chronic social defeat stress in female mice.Neuropsychopharmacology. 2018; 43: 1276-1283Crossref PubMed Scopus (104) Google Scholar,39.Takahashi A. et al.Establishment of a repeated social defeat stress model in female mice.Sci. Rep. 2017; 7: 12838Crossref PubMed Scopus (123) Google Scholar]. Moreover, development of susceptible versus resilient responses to CSDS does not require physical defeat per se: C57BL/6J mice that simply witness another C57BL/6J mouse being defeated develop a similar ratio of susceptibility versus resilience [40.Warren B.L. et al.Neurobiological sequelae of witnessing stressful events in adult mice.Biol. Psychiatry. 2013; 73: 7-14Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar]. a cluster of primary sensory neurons that generate signals (including pain) from the periphery and transmit them to the spinal cord. a powerful electrophysiological method to compare the effects of wild-type and variant ion channels within the same cell. It can be used to assess the role of mutant channels in modulating excitability of neurons. mediate the interactions between environmental exposures and an individual’s genome sequence. Environmentally mediated alterations are, for example, changes in histone-modifying enzymes, chromatin-remodeling proteins, DNA methylation, and miRNAs. controls secretion of glucocorticoids by the body; has long been known as a major feature of mammalian stress responses and was more recently implicated in stress resilience. also called the ‘Man on Fire’ syndrome; an autosomal dominant disorder characterized by episodes of excruciating burning pain triggered by mild warmth, which is usually innocuous, such as wearing socks or a sweater, or entering a room at 70°F. The feeling is described ‘as if hot lava has been poured into the body’. People with IEM tend to immerse their limbs in cold water or even ice to alleviate pain, which might imply abnormal impulse generation in axon terminals within the skin. there are different pain assessment scales for different patient types. Generally higher numbers indicate more severe pain. A KV7 channel potentiator that has been marketed for the treatment of epilepsy but rarely used due to adverse effects. Retigabine selectively targets specific KV7 subtypes in the brain implicated in stress resilience.