Peptidergic modulation of pain and anxiety: forebrain relaxin-3/RXFP3 networks and descending control of nociception in mice

Persistent pain can hinder normal function and behaviour, with a negative impact on quality-of-life. In persistent pain conditions, patients develop conditions such as anxiety, which worsens pain sensation, creating a feedback loop between pain and this comorbid state. Anxiety is linked to altered function in brain areas innervated by relaxin-3 neurons. Indeed, activation of its receptor, Relaxin/Insulin Family Peptide Receptor 3 (RXFP3), can alter arousal, stress- and anxiety-related and reward-seeking behaviours in rodents. These data suggest a possible link between RXFP3 activity and control of pain sensitivity. Thus, these studies assessed the effect of RXFP3 activation/inhibition on the control of mechanical and thermal pain sensitivity in normal and persistent pain conditions in mice. Intracerebroventricular (icv) administration of RXFP3 agonist peptide reduced mechanical, but not thermal, pain sensation in C57BL/6J mouse model of inflammatory pain (n = 5 mice/group,p < 0.01). These effects were associated with decreased activity of nociceptive neurons in spinal cord (n = 6 mice, p < 0.05). In addition, RXFP3 antagonist augmented mechanical and thermal pain sensitivity (n = 7 mice/group, p > 0.05). These data suggest that relaxin-3 provides a tonic drive to maintain mechanical and thermal pain thresholds. In parallel, we sought to identify the neuronal circuits responsible for the observed effects. Using neural tract-tracing, we identified brain areas that receive relaxin-3 inputs,which in turn innervate the rostroventral medulla (RVM), a region that gates descending pain control. These regions include anterior cingulate cortex, central amygdala, bed nucleus of the stria terminalis and hypothalamus, which are functionally related to pain sensation and comorbidities. Together, these data suggest RXFP3 as a therapeutic target for pain management, and further studies of the specific circuits and mechanisms involved are warranted.