Dynamic interactions between plasma IL-1 family cytokines and central endogenous opioid neurotransmitter function in humans

Evidence in animal models suggests IL-1 family cytokines interact with central endogenous opioid neurotransmitter systems, inducing or perpetuating pathological states such as persistent pain syndromes, depression, substance use disorders, and their comorbidity. Understanding these interactions in humans is particularly relevant to understanding pathological states wherein this neurotransmitter system is implicated (ie, persistent pain, mood disorders, substance use disorders, etc). Here, we examined relationships between IL-1β, IL-1ra, and functional measures of the endogenous opioid system in 34 healthy volunteers, in the absence and presence of a standardized sustained muscular pain challenge, a psychophysical challenge with emotionally and physically stressful components. Mu-opioid receptor availability in vivo was examined with [(11)C]carfentanil positron emission tomography (PET) scanning. Sex and neuroticism impacted IL-1 family cytokines; higher baseline IL-1β and IL-1ra was identified in females with lower neuroticism. Higher baseline IL-1β was also associated with reduced μ-opioid receptor availability (amygdala) and greater pain sensitivity. The pain challenge increased IL-1β in females with high neuroticism. Strong associations between IL-1ra (an anti-nociceptive cytokine) and μ-opioid receptor activation (VP/NAcc) were identified during the pain challenge and the resulting analgesic effect of μ-opioid receptor activation was moderated by changes in IL-1β whereby volunteers with greater pain induced increase in IL-1β experienced less endogenous opioid analgesia. This study demonstrates the presence of relationships between inflammatory factors and a specific central neurotransmitter system and circuitry, of relevance to understanding interindividual variations in regulation of responses to pain and other physical and emotional stressors.