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Pharmacological rescue of nociceptive hypersensitivity and oxytocin analgesia impairment in a rat model of neonatal maternal separation

Melchior, Megganea; Juif, Pierre-Erica; Gazzo, Géraldinea; Petit-Demoulière, Nathaliea; Chavant, Virginiea,b; Lacaud, Adriena; Goumon, Yannicka,b; Charlet, Alexandrea,c; Lelièvre, Vincenta; Poisbeau, Pierricka,*

doi: 10.1097/j.pain.0000000000001375
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Oxytocin (OT), known for its neurohormonal effects around birth, has recently been suggested for being a critical determinant in neurodevelopmental disorders. This hypothalamic neuropeptide exerts a potent analgesic effect through an action on the nociceptive system. This endogenous control of pain has an important adaptive value but might be altered by early life stress, possibly contributing to its long-term consequences on pain responses and associated comorbidities. We tested this hypothesis using a rat model of neonatal maternal separation (NMS) known to induce long-term consequences on several brain functions including chronic stress, anxiety, altered social behavior, and visceral hypersensitivity. We found that adult rats with a history of NMS were hypersensitive to noxious mechanical/thermal hot stimuli and to inflammatory pain. We failed to observe OT receptor–mediated stress-induced analgesia and OT antihyperalgesia after carrageenan inflammation. These alterations were partially rescued if NMS pups were treated by intraperitoneal daily injection during NMS with OT or its downstream second messenger allopregnanolone. The involvement of epigenetic changes in these alterations was confirmed since neonatal treatment with the histone deacetylase inhibitor SAHA, not only normalized nociceptive sensitivities but also restored OT receptor–mediated stress-induced analgesia and the endogenous antihyperalgesia in inflamed NMS rats. There is growing evidence in the literature that early life stress might impair the nociceptive system ontogeny and function. This study suggests that these alterations might be restored while stimulating OT receptor signaling or histone deacetylase inhibitors, using molecules that are currently available or part of clinical trials for other pathologies.

Maternal separation renders adult rats hypersensitive to noxious stimuli and incapable to recruit oxytocin analgesic controls. Rescue is achieved by neonatal treatments with oxytocin, allopregnanolone, or histone deacetylase inhibitors.

aCentre National de la Recherche Scientifique, University of Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France

bMass Spectrometry Facilities of the CNRS UPR3212, Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique, Strasbourg, France

cUniversity of Strasbourg Institute for Advanced Study, Strasbourg, France

Corresponding author. Address: CNRS UPR-3212, Institut des Neurosciences Cellulaires et Intégratives (INCI), Research group, Plasticity of Pain Controls, 5 rue Blaise Pascal, Strasbourg 67000, France. Tel.: (+33) 3 68 85 14 76; fax: (+33) 3 88 61 33 47. E-mail address: poisbeau@inci-cnrs.unistra.fr (P. Poisbeau).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

Received December 11, 2017

Accepted June 20, 2018

© 2018 International Association for the Study of Pain
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