SUMMARY. The current proposal addresses fundamental neurophysiological questions related to oxytocin (OXT) pharmacology and pain neurobiology in normal and nerve injury settings. We aim to define (a) the OXT PK/PD relationships on fast-conducting afferents (A-fibers), both tactile (LTMRs: low threshold mechanoreceptors) and nociceptive (AHTMRs: A-fiber high threshold mechanoreceptors), (b) to study the effects of L5 SNL at the peak of maximal sensitization (week 2) on injured (L5) and uninjured (L4) afferents and the OXT-mediated modulation of these sensitization process and (c) to correlate the OXT-induced modulation of sensibility (L4) and excitability (L5) with the animal behavior (normal or abnormal) after recovery (weeks 8-12). Our working hypothesis has two parts: 1) that A-fibers response to injury (LTMR: desensitization and AHTMR: sensitization) is critical for the development of a peripheral mediated neuropathic state and 2) that OXT can resolve this state and modulate the recovery by rescuing these afferents from they abnormal excitability. We anticipate that this research will contribute to understanding the physiological effects of OXT, how much of overall central effects can be explained by the OXT peripheral modulation (interaction with Project 2, Dr. Martin), and how these effects can be optimized for the treatment of pain in human patients (interaction with Project 3, Dr. Eisenach).