Refining Oxytocin Therapy for Pain: Context is Key

Intrathecal oxytocin (OT) is in clinical trials as an opioid alternative for chronic pain treatment. Our work in mice
suggests that coupling intrathecal oxytocin with manual therapies (i.e. massage) optimizes the analgesic
properties of oxytocin. This project provides the framework to support this combination therapy by concentrating
on the spinal cord circuit mechanisms by which oxytocin alleviates pain. Our preliminary studies suggest that
oxytocin-specific spinal cord circuits are embedded within a previously uncharacterized dorsal horn
nociceptive/affective touch circuit. We will carry out three complementary sets of experiments to test the overall
hypothesis that oxytocin alleviates pain by balancing excitation, inhibition, nociception, and affective touch to
sculpt the activity of spinal projections systems that carry both negative valences (associated with noxious
stimuli), and signals associated with positive valence (like the pleasurable properties of touch). Pharmacological
and behavioral studies in rodents suggest that spinal cord oxytocin receptors (OTRs) mediate intrathecal
oxytocin-induced analgesia. In Aim 1 we map the distribution of OTR+ interneurons within the dorsal horn of
female and male mice, rats, and humans. In Aim 2, we map the specific input/output profiles of OTR+INs. Here
we test the hypothesis that inhibitory and excitatory OTR+INs integrate peripheral nociceptive/affective touch
information with OT to differentially regulate the activity of molecularly defined Lamina I projection neurons. In
Aim 3 we assay the contribution of OT spinal cord circuits to both sensory-evoked reflexes and affective-
motivational pain. For Aim 3 we implement our recently developed computational approaches to scale sensory-
reflexive and affective-motivational pain. Results from our human tissue studies will inform how our
interpretations of our rodent studies may be applied to human therapies. Based on our unique expertise in touch-
specific spinal cord circuits, access to a large repertoire of spinal cord-specific tools, and behavior analytics that
match the granularity of our circuit dissection techniques, we are uniquely poised to provide the theoretical
framework for this combination therapy. In addition to informing context and condition for OT delivery, this work
may also be used in the clinic to adjust OT dosage and delivery method. This project is impactful for several
other reasons: 1) using computer vision/machine learning we will uncover the specific aspects of the pain
experience that are alleviated by spinal cord OT, and assess efficacy against other analgesics; 2) our
computational approaches to objectively scale rodent pain can be easily shared and implemented across
research groups, serving as a blueprint to standardize rodent pain assessment (see Resource Sharing); 3) our
general approach and model can serve as a basic blueprint for testing how other neuromodulators are
functionally integrated into spinal cord circuits of touch and nociception; and; 4) this type of foundational work
informs innovative approaches to disentangle the sensory from the emotional experiences of pain, inspiring new
therapies to treat each uniquely.

Grant Number: 5R01NS124799-04
NIH Institute/Center: NIH
Principal Investigator: Victoria Abraira