Abstract
Oxytocin possesses several physiological and social functions, among which an important analgesic effect. For this purpose, oxytocin binds mainly to its unique receptor, both in the central nervous system and in the peripheral nociceptive terminal axon in the skin. However, despite its interesting analgesic properties and its current use in clinics to facilitate labor, oxytocin is not used in pain treatment. Indeed, it is rapidly metabolized, with a half-life in the blood circulation estimated at five minutes and in cerebrospinal fluid around twenty minutes in humans and rats. Moreover, oxytocin itself suffers from several additional drawbacks: a lack of specificity, an extremely poor oral absorption and distribution, and finally, a lack of patentability. Recently, a first non-peptide full agonist of oxytocin receptor (LIT-001) of low molecular weight has been synthesized with reported beneficial effect for social interactions after peripheral administration. In the present study, we report that a single intraperitoneal administration of LIT-001 in a rat model induces a long-lasting reduction in inflammatory pain-induced hyperalgesia symptoms, paving the way to an original drug development strategy for pain treatment.
Highlights
Oxytocin (OT) is a 9–amino acid neuropeptide that plays an important role in several physiological and social functions
In nociception and pain, OT has central and peripheral targets depending on the releasing pathway: plasmatic released OT has in vivo antinociceptive action through reduction of C fiber excitability leading to a reduction of activity of wide dynamic range (WDR) spinal sensory neurons[10] whereas OT released by fibers originating from PVN directly on WDR neurons inhibits sensory processing and produces analgesia in inflammatory pain model[11,12]
LIT-001 is a pyrazolobenzodiazepine derivative with a non-peptide chemical structure and a low molecular weight (MW) compared to oxytocin (MW = 531 vs. 1007, respectively, Fig. 1a)
Summary
Oxytocin (OT) is a 9–amino acid neuropeptide that plays an important role in several physiological and social functions. In nociception and pain, OT has central and peripheral targets depending on the releasing pathway: plasmatic released OT has in vivo antinociceptive action through reduction of C fiber excitability leading to a reduction of activity of wide dynamic range (WDR) spinal sensory neurons[10] whereas OT released by fibers originating from PVN directly on WDR neurons inhibits sensory processing and produces analgesia in inflammatory pain model[11,12]. In these models, direct activation of parvocellular OT neuron by optogenetics, resulting in central and peripheral release of endogenous OT, produced a significant OTR-dependent analgesia[11].
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