NIH – Mechanistic investigations of psychosocial stress effects on opioid use patterns (R01, R21- Clinical Trial Optional)

February 2, 2018 by School of Medicine Webmaster

The following description was taken from the R01 version of this FOA.

Psychosocial stress, defined here as socioenvironmental demands that tax the adaptive capacity of the individual (e.g., low socioeconomic status, childhood adversity, bullying), has repeatedly been linked to substance use disorders (SUDs). Neighborhood poverty and social support are shown to influence substance use patterns. Among smokers, multiple psychosocial stressors are associated with relapse, and acute psychosocial stress has been demonstrated to enhance cigarette craving and smoking behavior. Similarly, psychosocial stress has been associated with greater risk of relapse in individuals with alcohol and cocaine use disorders. Recent findings suggest that OUD might also be influenced by psychosocial stress, although the exact relationship and underlying mechanisms remain poorly understood.

In light of the current opioid epidemic in the United States, there is an urgent need to understand how psychosocial stress influences the risk for opioid misuse, abuse, and use disorder. According to the 2014 National Survey on Drug Use and Health (NSDUH), over 4 million Americans engaged in non-medical use of prescription opioids in the previous month, and approximately 1.9 million Americans met criteria for OUD. Further, according to the Center for Disease Control (CDC), deaths from drug overdose in the US exceeded 60,000 last year, surpassing the number of AIDS-related deaths at the height of the HIV/AIDS epidemic. Another recent CDC report indicates that areas with the largest number of filled prescriptions for pain medications also have higher rates of poverty and unemployment, implicating psychosocial stressors as factors that exacerbate opioid use patterns across the country. Notably, relatively few mechanistic studies have investigated the relationship between psychosocial stress and substance use disorders, of which only a fraction pertains to OUDs specifically.

This funding opportunity announcement seeks to address two specific mechanistic pathways via which psychosocial stress may modulate opioid use trajectories. The first pathway is through its effects on cognitive and affective systems that are also altered in OUDs. Stressful environments have been linked to impairments in reasoning, memory, inhibitory and cognitive control, and negative affect. Acute poverty, for example, has been shown to immediately impact performance on tasks measuring intelligence and cognitive control. Relatedly, there is substantial co-morbidity between OUD and stress-related affective disorders, including depression, anxiety and PTSD. Many neurobiological substrates and circuits that are thought to mediate cognitive and affective aspects of addiction are impacted by psychosocial stress. Taken together, these findings suggest that more research is warranted on the role of cognitive and affective systems mediating the effects of psychosocial stress on opioid use trajectories.

Psychosocial stress can also influence opioid use trajectories through its effects on pain processing. Of relevance here, adverse childhood experiences have been associated with an increased prevalence of pain-related medical conditions during adulthood and many individuals with stress-related psychiatric disorders have co-morbid chronic pain syndromes. This may be a consequence of overlapping neural circuits or substrates that are engaged by psychosocial stress and pain and that have been implicated in OUD. Recent estimates suggest that the rates of opioid misuse in patients with chronic pain range from 15-26%. Importantly, and germane to the discussion above, negative affect and the reduced ability to cope with negative emotions in pain appear to increase opioid misuse rates. Further research is needed to understand how the effects of psychosocial impacts on cognitive and affective components of pain may influence the opioid use trajectory. This knowledge may advance prevention and treatment strategies in chronic pain populations.

Research Objectives

Together, the findings discussed above provide a compelling rationale for the need to elucidate the mechanisms by which psychosocial stress can affect vulnerability to OUD through its modulation of affective/cognitive and/or pain systems. Applications investigating relevant mechanisms related to neurocircuitry, structural and functional neuroplasticity, receptor adaptation, neuroimmune and glial plasticity, and genetics and epigenetics are encouraged. Also of interest are applications seeking to elucidate mechanisms related to vulnerability and resilience to the effects of psychosocial stress on the two pathways of interest.

This FOA encourages both basic science research in animal models and human-based laboratory studies in human subjects. All applicants are advised to include an emphasis on OUD trajectories, and to include a component on psychosocial stress-induced changes in cognitive/affective function and/or chronic pain. For the purposes of this FOA, research on substances of abuse other than opioids are strongly discouraged.

Clinical Studies

Clinical studies investigating the role of psychosocial stressors such as early life adversity, poverty, unemployment, social isolation, discrimination (based on race, gender, body weight, etc.), environmental instability (e.g., food insecurity or social instability), and psychological trauma in OUD trajectories are encouraged. Research applications that emphasize non-psychosocial stressors, such as environmental hazards (e.g., lead exposure), are strongly discouraged. Topics of interest include, but are not limited to:

  • Developmental windows during which psychosocial stress maximally increases vulnerability to OUD or altered pain sensitivity
  • Mechanisms through which various moderators (e.g., coping strategies, genetic factors) influence the effects of psychosocial stress on OUD trajectories
  • Contributions of co-morbid psychiatric disorders to pain processing and risk for OUD
  • Psychosocial stress effects on brain network-level dynamics related to reward and punishment processing, executive function, decision-making, or compulsive behavior in OUD patients
  • Epigenetic effects of psychosocial stress that could contribute to its effects on pain sensitivity or OUD
  • Neurobiological changes that mediate increased resiliency to effects of psychosocial stress among chronic pain patients
  • Computational models of neurocognitive mechanisms underlying the effects of psychosocial stress on opioid use trajectories
  • Sex or gender differences in vulnerability and resilience to the effects of psychosocial stressors on opioid use outcomes

Preclinical Studies

All preclinical applications are advised to include: (1) an emphasis on psychosocial stress, (2) a measure of opioid use liability, and (3) a component on psychosocial stress-induced changes in negative affect, cognitive function, or pain sensitivity. Applications are encouraged to include animal models of chronic or repeated psychosocial stress. Research applications that include restraint stress, foot shock, predator odor stress, or pharmacological manipulations that elevate stress are strongly discouraged. Topics of interest include, but are not limited to:

  • Individual differences in the endogenous opioid system as it relates to psychosocial stress induced changes in the OUD trajectory
  • Genetic factors that determine propensity to develop OUDs after exposure to psychosocial stress
  • The effects of psychosocial stress on gene function (e.g. transcription, epigenetic modifications, non-coding RNAs, chromatin structure) in relevant brain tissues
  • The impact of psychosocial stress on receptor signaling and trafficking to affect OUD vulnerability
  • Identification and functional characterization of circuitry engaged by psychosocial stress that overlaps with pain circuits or circuits involved in OUD
  • Effects of psychosocial stress on neuroimmune factors that influence pain or OUD
  • Mechanisms through which negative affect moderates the transition from acute to chronic pain and impacts OUD trajectories
  • Individual differences in vulnerability to psychosocial stress-induced changes that bias opioid use liability, including role of coping strategy
  • Sex differences in psychosocial stress-induced changes in pain sensitivity or affective/cognitive outcomes as they relate to OUD

Examples of psychosocial stressors include, but are not limited to:

  • Social defeat
  • Maternal neglect
  • Social Isolation
  • Environmental instability (e.g., food insecurity or social instability)
  • Witnessing trauma of a conspecific

Whenever possible, animal models of voluntary, chronic intake of opioids are encouraged. Research relevant to this FOA should pertain to at least one of the stages of the opioid use trajectory, including acquisition, escalation, and relapse. Examples of animal models of interest include, but are not limited to:

  • Escalation
  • Abstinence
  • Cue, stress, or drug-induced reinstatement of opioid seeking; incubation of drug craving
  • Motivated responding (economic demand procedures, progressive ratio schedule of reinforcement, continued seeking despite drug unavailability, effort discounting)
  • Persistent drug seeking behaviors in face of adverse consequences
  • Choice between opioids and alternate reinforcers

Deadlines:  standard dates and standard AIDS dates apply.


Filed Under: Funding Opportunities