Central Control Of Pain And Inflammation Through A Hunger Circuit

Homeostasis is established through bidirectional communication between the periphery and the central nervous system. To maintain homeostasis, some biological drives can become prioritized over others. This changing balance between biological drives encourages peak performance and survival. However, when homeostasis is disturbed, chronic inflammatory diseases such as obesity, chronic pain, and arthritis can arise. We became interested in understanding if competing biological drives could be leveraged for therapeutic purposes. Food restriction inhibits inflammation; therefore, we explored how hunger and feeding neural circuits affect responses to noxious agents. Our first study investigated the role of hunger to alleviate pain behavior. We found that hunger significantly reduces time spent licking during the inflammatory phase of a formalin pain assay but leaves intact pain responses to acute threats. We next evaluated if hypothalamic hunger neurons are involved in this behavioral change. Stimulation of agouti-related protein expressing (AgRP) neurons significantly reduced formalin pain behavior. To determine the central nodes that mediate this effect, we systematically screened AgRP neuron projections for their ability to suppress pain. Only AgRP neurons projecting to the hindbrain parabrachial nucleus was able to reduce inflammatory pain behavior. Our second study investigated the role of hunger to influence inflammatory responses of an injury site. Using two models of localized inflammation, we found that food deprivation robustly reduces inflammation, pro-inflammatory cytokine levels, and associated temperature increases induced by injection of noxious stimuli [complete Freund’s adjuvant (CFA) or formalin]. Activation of AgRP neurons recapitulated the effect of food deprivation on inflammation. We then evaluated the role of each AgRP axonal target structure to reduce inflammation. Interestingly, stimulation of AgRP neurons that project to the paraventricular nucleus of the hypothalamus or the parabrachial nucleus were sufficient to reduce CFA-induced inflammation. Finally, we identified the vagus nerve as a key pathway for the anti-inflammatory effect of hunger. We propose that hunger, through AgRP neurons, inhibits pro-inflammatory responses from the central nervous system and changes the output of efferent vagal fibers. This body of work reveals a central node for the reduction of pain and inflammation, highlighting a novel role for hypothalamic circuits to influence injury responses.