Functional Effects of the Relaxin-3/RXFP-3 Pathway on the Affective Dimension of Chronic Pain
Summary
Chronic pain, defined as pain lasting more than 3-6 months, affects approximately 20% of the
global population and has a profound socioeconomic effect, inducing a severe drop in the
quality of life of patients with few effective treatment and management options available. The
Relaxin-3 neuropeptide has been identified as a potential pharmacotherapeutic agent, having
been shown to attenuate hyperalgesia stemming from CFA-induced chronic pain in mice in the
Von Frey and Plantar behavioral assays. However, it is unclear whether Relaxin-3 is able to
induce analgesia against spontaneous pain and to modulate the affective-emotional dimension
of nociception, two key components for treatment of chronic pain. Here, we developed a
modified Conditioned Place Preference paradigm utilizing pain relief as a reward to assess
Relaxin-3’s effects on these facets of chronic pain. We found that Relaxin-3 is able to induce
Conditioned Place Preference in CFA-treated mice, but not in NaCl-treated mice, indicating that
it is reducing spontaneous pain and modulating the affective dimension of nociception in this
chronic pain mouse model . We additionally utilized this modified CPP in conjunction with a
pharmacogenetic technique employing DREADD/CNO to examine the Relaxin-3 circuitry,
finding strong evidence that Relaxin-3 inhibits Somatostatin neurons in the BLA in its pain
modulation pathway. Finally, we induced continuous activation of Relaxin-3 Receptor RXFP-3 in
the ACC through the tonic production of Relaxin-3 agonist R3/I5 in order to assess its effects on
the development of chronic pain. Utilizing the Von Frey and Plantar nociceptive assays, we
found that tonic R3/I5 release attenuated CFA-induced hyperalgesia in a manner similar to
intracerebral injections of Relaxin-3 agonist A5, the current golden standard for Relaxin-3
research, without apparent extraneous effects in regards to behavior or the development of
chronic pain in mice with or without pain, and as such propose it as an alternative to A5
injections.