{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T22:07:37Z","timestamp":1792447657713,"version":"4.5.0"},"reference-count":97,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T00:00:00Z","timestamp":1724112000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["26463062"],"award-info":[{"award-number":["26463062"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Pain is a major non-motor symptom of Parkinson\u2019s disease (PD). Alterations in the descending pain inhibitory system (DPIS) have been reported to trigger hyperalgesia in PD patients. However, the underlying mechanisms remain unclear. In the current study, dopaminergic nigrostriatal lesions were induced in rats by injecting 6-hydroxydopamine (6-OHDA) into their medial forebrain bundle. The neural mechanisms underlying changes in nociception in the orofacial region of 6-OHDA-lesioned rats was examined by injecting formalin into the vibrissa pad. The 6-OHDA-lesioned rats were seen to exhibit increased frequency of face-rubbing and more c-Fos immunoreactive (c-Fos-IR) cells in the trigeminal spinal subnucleus caudalis (Vc), confirming hyperalgesia. Examination of the number of c-Fos-IR cells in the DPIS nuclei [including the midbrain ventrolateral periaqueductal gray, the locus coeruleus, the nucleus raphe magnus, and paraventricular nucleus (PVN)] showed that 6-OHDA-lesioned rats exhibited a significantly lower number of c-Fos-IR cells in the magnocellular division of the PVN (mPVN) after formalin injection compared to sham-operated rats. Moreover, the 6-OHDA-lesioned rats also exhibited significantly lower plasma oxytocin (OT) concentration and percentage of oxytocin-immunoreactive (OT-IR) neurons expressing c-Fos protein in the mPVN and dorsal parvocellular division of the PVN (dpPVN), which secrete the analgesic hormone OT upon activation by nociceptive stimuli, when compared to the sham-operated rats. The effect of OT on hyperalgesia in 6-OHDA-lesioned rats was examined by injecting formalin into the vibrissa pad after intracisternal administration of OT, and the findings showed a decrease in the frequency of face rubbing and the number of c-Fos-IR cells in the Vc. In conclusion, these findings confirm presence of hyperalgesia in PD rats, potentially due to suppression of the analgesic effects of OT originating from the PVN.<\/jats:p>","DOI":"10.1371\/journal.pone.0300081","type":"journal-article","created":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T13:47:52Z","timestamp":1724161672000},"page":"e0300081","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Changes in the analgesic mechanism of oxytocin can contribute to hyperalgesia in Parkinson\u2019s disease model 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Delaville","year":"2011","journal-title":"Front Syst Neurosci."},{"key":"pone.0300081.ref005","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1136\/jnnp.2007.120212","article-title":"Levodopa raises objective pain threshold in Parkinson\u2019s disease: a RIII reflex study","volume":"78","author":"A Gerdelat-Mas","year":"2007","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"pone.0300081.ref006","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.pharep.2017.05.016","article-title":"Depressive-like neurochemical and behavioral markers of Parkinson\u2019s disease after 6-OHDA administered unilaterally to the rat medial forebrain bundle.","volume":"69","author":"K Kami\u0144ska","year":"2017","journal-title":"Pharmacol Rep"},{"key":"pone.0300081.ref007","first-page":"167","article-title":"Overview of the extranigral aspects of Parkinson disease","volume":"66","author":"SY Lim","year":"2009","journal-title":"Arch Neurol"},{"key":"pone.0300081.ref008","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1007\/s00415-010-5812-0","article-title":"Spontaneous pain, pain threshold, and pain tolerance in Parkinson\u2019s disease","volume":"258","author":"SZ Marsala","year":"2011","journal-title":"J Neurol"},{"key":"pone.0300081.ref009","first-page":"231","article-title":"Pain sensitivity and descending inhibition of pain in Parkinson\u2019s disease and progressive supranuclear palsy","volume":"116","author":"V Mylius","year":"2009","journal-title":"J Neural Transm"},{"key":"pone.0300081.ref010","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1111\/j.1526-4637.2010.00866.x","article-title":"Response to heat pain stimulation in idiopathic Parkinson\u2019s disease","volume":"11","author":"R Nandhagopal","year":"2010","journal-title":"Pain Med"},{"key":"pone.0300081.ref011","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1002\/mds.23458","article-title":"Facilitated temporal summation of pain at spinal level in Parkinson\u2019s disease","volume":"26","author":"A Perrotta","year":"2011","journal-title":"Mov Disord"},{"key":"pone.0300081.ref012","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1111\/j.1460-9568.2004.03622.x","article-title":"Striatal dopamine D2\/D3 receptor availability correlates with individual response characteristics to pain","volume":"20","author":"A Pertovaara","year":"2004","journal-title":"Eur J Neurosci"},{"key":"pone.0300081.ref013","doi-asserted-by":"crossref","first-page":"e0136541","DOI":"10.1371\/journal.pone.0136541","article-title":"Pain in Parkinson\u2019s disease: A cross-sectional study of its prevalence, types, and relationship to depression and quality of life.","volume":"10","author":"P Valkovic","year":"2015","journal-title":"PLOS ONE."},{"key":"pone.0300081.ref014","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/nrneurol.2012.54","article-title":"Pains in Parkinson disease-many syndromes under one umbrella.","volume":"8","author":"G Wasner","year":"2012","journal-title":"Nat Rev Neurol."},{"key":"pone.0300081.ref015","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1002\/brb3.214","article-title":"Lesion of the dopaminergic nigrostriatal pathway induces trigeminal dynamic mechanical allodynia","volume":"4","author":"W Dieb","year":"2014","journal-title":"Brain Behav"},{"key":"pone.0300081.ref016","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s10194-016-0607-z","article-title":"Nigrostriatal dopaminergic depletion increases static orofacial allodynia","volume":"17","author":"W Dieb","year":"2016","journal-title":"J Headache Pain"},{"key":"pone.0300081.ref017","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.expneurol.2019.02.007","article-title":"Parkinson\u2019s disease and pain: modulation of nociceptive circuitry in a rat model of nigrostriatal lesion","volume":"315","author":"RA Domenici","year":"2019","journal-title":"Exp Neurol"},{"key":"pone.0300081.ref018","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.neures.2015.01.006","article-title":"Neural mechanism underlying hyperalgesic response to orofacial pain in Parkinson\u2019s disease model rats","volume":"96","author":"H Maegawa","year":"2015","journal-title":"Neurosci Res"},{"key":"pone.0300081.ref019","doi-asserted-by":"crossref","first-page":"e0225928","DOI":"10.1371\/journal.pone.0225928","article-title":"Bilateral Parkinson\u2019s disease model rats exhibit hyperalgesia to subcutaneous formalin administration into the vibrissa pad.","volume":"14","author":"H Maegawa","year":"2019","journal-title":"PLOS ONE."},{"key":"pone.0300081.ref020","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.neures.2005.01.005","article-title":"Unilateral lesions of mesostriatal dopaminergic pathway alters the withdrawal response of the rat hindpaw to mechanical stimulation","volume":"52","author":"R Takeda","year":"2005","journal-title":"Neurosci Res"},{"key":"pone.0300081.ref021","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.brainres.2007.08.012","article-title":"Behavioral responses and Fos activation following painful stimuli in a rodent model of Parkinson\u2019s disease","volume":"1176","author":"C Tassorelli","year":"2007","journal-title":"Brain Res"},{"key":"pone.0300081.ref022","doi-asserted-by":"crossref","first-page":"e73022","DOI":"10.1371\/journal.pone.0073022","article-title":"Bilateral descending hypothalamic projections to the spinal trigeminal nucleus caudalis in rats.","volume":"8","author":"K Abdallah","year":"2013","journal-title":"PLOS ONE"},{"key":"pone.0300081.ref023","first-page":"6383240","article-title":"Restoring spinal noradrenergic inhibitory tone attenuates pain hypersensitivity in a rat model of Parkinson\u2019s disease","volume":"2016","author":"LF Cao","year":"2016","journal-title":"Neural Plast"},{"key":"pone.0300081.ref024","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.parkreldis.2012.11.009","article-title":"Pain in Parkinson disease: a review of the literature","volume":"19","author":"A Fil","year":"2013","journal-title":"Parkinsonism Relat Disord"},{"key":"pone.0300081.ref025","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/S0301-0082(02)00009-6","article-title":"Descending control of pain","volume":"66","author":"MJ Millan","year":"2002","journal-title":"Prog Neurobiol"},{"key":"pone.0300081.ref026","first-page":"155","article-title":"Central nervous system plasticity and persistent pain","volume":"13","author":"K Ren","year":"1999","journal-title":"J Orofac Pain"},{"key":"pone.0300081.ref027","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1002\/cne.20797","article-title":"Trigeminal transition zone\/rostral ventromedial medulla connections and facilitation of orofacial hyperalgesia after masseter inflammation in rats","volume":"493","author":"S Sugiyo","year":"2005","journal-title":"J Comp Neurol"},{"key":"pone.0300081.ref028","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.expneurol.2019.04.015","article-title":"Monoaminergic regulation of nociceptive circuitry in a Parkinson\u2019s disease rat model","volume":"318","author":"ACP Campos","year":"2019","journal-title":"Exp Neurol"},{"key":"pone.0300081.ref029","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.conb.2014.07.010","article-title":"Descending modulation of pain: the GABA disinhibition hypothesis of analgesia","volume":"29","author":"BK Lau","year":"2014","journal-title":"Curr Opin Neurobiol"},{"key":"pone.0300081.ref030","doi-asserted-by":"crossref","first-page":"3779","DOI":"10.1172\/JCI43766","article-title":"Central modulation of pain","volume":"120","author":"MH Ossipov","year":"2010","journal-title":"J Clin 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Neuroendocrinol"},{"key":"pone.0300081.ref034","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.neuroscience.2017.05.015","article-title":"Comparison of the induction of C-FOS-EGFP and FOS protein in the rat spinal cord and hypothalamus resulting from subcutaneous capsaicin or formalin injection","volume":"356","author":"Y Motojima","year":"2017","journal-title":"Neuroscience"},{"key":"pone.0300081.ref035","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1111\/jne.12252","article-title":"Neuroendocrine-autonomic integration in the paraventricular nucleus: novel roles for dendritically released neuropeptides","volume":"27","author":"JE Stern","year":"2015","journal-title":"J Neuroendocrinol"},{"key":"pone.0300081.ref036","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3389\/fendo.2020.00043","article-title":"Acute mono-arthritis activates the neurohypophysial system and hypothalamo-pituitary adrenal axis in rats.","volume":"11","author":"H Nishimura","year":"2020","journal-title":"Front Endocrinol."},{"key":"pone.0300081.ref037","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1111\/j.0953-8194.2004.01172.x","article-title":"Regulatory mechanisms of corticotropin-releasing hormone and vasopressin gene expression in the hypothalamus","volume":"16","author":"K Itoi","year":"2004","journal-title":"J Neuroendocrinol"},{"key":"pone.0300081.ref038","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1677\/joe.0.1340327","article-title":"Stress and the hypothalamo-pituitary-adrenal axis: acute, chronic and immunological activation","volume":"134","author":"MS Harbuz","year":"1992","journal-title":"J Endocrinol"},{"key":"pone.0300081.ref039","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.brainres.2006.02.099","article-title":"The short chain sugar acid, 2-buten-4-olide, activates oxytocin-secreting neurons but not arginine vasopressin secreting neurons in the hypothalamus of rats","volume":"1086","author":"M Kawasaki","year":"2006","journal-title":"Brain Res"},{"key":"pone.0300081.ref040","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1146\/annurev.ne.06.030183.001413","article-title":"Hypothalamic integration: organization of the paraventricular and supraoptic nuclei","volume":"6","author":"LW Swanson","year":"1983","journal-title":"Annu Rev Neurosci"},{"key":"pone.0300081.ref041","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/S0079-6123(08)00429-9","article-title":"Chronic stress plasticity in the hypothalamic paraventricular nucleus","volume":"170","author":"JP Herman","year":"2008","journal-title":"Prog Brain Res"},{"key":"pone.0300081.ref042","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/0006-8993(90)90115-R","article-title":"Long-term survival of grafted cells, dopamine synthesis\/release, synaptic connections, and functional recovery after transplantation of fetal nigral cells in rats with unilateral 6-OHDA lesions in the nigrostriatal dopamine pathway","volume":"534","author":"H Nishino","year":"1990","journal-title":"Brain Res"},{"key":"pone.0300081.ref043","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/S0006-8993(97)01541-2","article-title":"Serotonergic activity in the rat striatum after intrastriatal transplantation of fetal nigra as measured by microdialysis","volume":"788","author":"Y Ishida","year":"1998","journal-title":"Brain Res"},{"key":"pone.0300081.ref044","doi-asserted-by":"crossref","first-page":"104","DOI":"10.3389\/fneur.2016.00104","article-title":"Contribution of pro-inflammatory cytokine signaling within midbrain periaqueductal gray to pain sensitivity in Parkinson\u2019s disease via GABAergic pathway","volume":"7","author":"XB Zhuang","year":"2016","journal-title":"Front Neurol"},{"key":"pone.0300081.ref045","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1080\/00207450701239210","article-title":"Patterns of FOS expression in the spinal cord and periaqueductal grey matter of 6OHDA-lesioned rats","volume":"118","author":"S Reyes","year":"2008","journal-title":"Int J Neurosci"},{"key":"pone.0300081.ref046","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.pain.2004.03.036","article-title":"Opiate anti-nociception is attenuated following lesion of large dopamine neurons of the periaqueductal grey: critical role for D-1 (not D2) dopamine receptors.","volume":"110","author":"JA Flores","year":"2004","journal-title":"Pain"},{"key":"pone.0300081.ref047","doi-asserted-by":"crossref","first-page":"349","DOI":"10.4196\/kjpp.2015.19.4.349","article-title":"Antinociceptive effects of transcytosed botulinum neurotoxin Type A on trigeminal nociception in rats","volume":"19","author":"HJ Kim","year":"2015","journal-title":"Korean J Physiol Pharmacol"},{"key":"pone.0300081.ref048","first-page":"1","volume-title":"The rat brain in stereotaxic coordinates. 6th ed","author":"G Paxinos","year":"2007"},{"key":"pone.0300081.ref049","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.neuroscience.2005.01.055","article-title":"A brainstem substrate for analgesia elicited by intraoral sucrose","volume":"133","author":"VCZ Anseloni","year":"2005","journal-title":"Neuroscience"},{"key":"pone.0300081.ref050","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1007\/s12035-014-9059-0","article-title":"The pronociceptive effect of paradoxical sleep deprivation in rats: evidence for a role of descending pain modulation mechanisms","volume":"53","author":"DH Tomim","year":"2016","journal-title":"Mol Neurobiol"},{"key":"pone.0300081.ref051","doi-asserted-by":"crossref","first-page":"e98382","DOI":"10.1371\/journal.pone.0098382","article-title":"Altered formalin-induced pain and Fos induction in the periaqueductal grey of preadolescent rats following neonatal LPS exposure","volume":"9","author":"I Zouikr","year":"2014","journal-title":"PLOS ONE"},{"key":"pone.0300081.ref052","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.neulet.2004.05.112","article-title":"Oxytocin levels in the plasma and cerebrospinal fluid of male rats: effects of circadian phase, light and stress","volume":"367","author":"K Devarajan","year":"2004","journal-title":"Neurosci Lett"},{"key":"pone.0300081.ref053","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.pain.2008.08.015","article-title":"PVN electrical stimulation prolongs withdrawal latencies and releases oxytocin in cerebrospinal fluid, plasma, and spinal cord tissue in intact and neuropathic rats","volume":"140","author":"G Mart\u00ednez-Lorenzana","year":"2008","journal-title":"Pain"},{"key":"pone.0300081.ref054","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1111\/j.1471-4159.1983.tb11293.x","article-title":"Determination of brain 5-hydroxytryptamine turnover in freely moving rats using repeated sampling of cerebrovascular-fluid","volume":"40","author":"GS Sarna","year":"1983","journal-title":"J Neurochem"},{"key":"pone.0300081.ref055","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1016\/j.neuroscience.2008.03.041","article-title":"Activation of microglia and p38 mitogen-activated protein kinase in the dorsal column nucleus contributes to tactile allodynia following peripheral nerve injury","volume":"153","author":"R Terayama","year":"2008","journal-title":"Neuroscience"},{"key":"pone.0300081.ref056","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0006-8993(03)03019-1","article-title":"Involvement of oxytocin in spinal antinociception in rats with inflammation","volume":"983","author":"SQ Yu","year":"2003","journal-title":"Brain Res"},{"key":"pone.0300081.ref057","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.brainres.2008.03.053","article-title":"Nociceptive behavioral responses to chemical, thermal and mechanical stimulation after unilateral, intrastriatal administration of 6-hydroxydopamine","volume":"1213","author":"EH Chudler","year":"2008","journal-title":"Brain Res"},{"key":"pone.0300081.ref058","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.neubiorev.2003.12.003","volume":"28","author":"P Raboisson","year":"2004","journal-title":"Neurosci Biobehav Rev"},{"key":"pone.0300081.ref059","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.neuroscience.2005.03.021","article-title":"Elimination of neurokinin-1 receptor neurons in caudal nucleus reverses the effects of systemic bicuculline on C-fos expression in rat trigeminal sensory nucleus: I. High intensity electrical stimulation of the trigeminal ganglion","volume":"133","author":"T Abe","year":"2005","journal-title":"Neuroscience"},{"key":"pone.0300081.ref060","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.2147\/JPR.S165969","article-title":"Chronic 17 beta-estradiol pretreatment has pronociceptive effect on behavioral and morphological changes induced by orofacial formalin in ovariectomized rats","volume":"11","author":"A Fejes-Szab\u00f3","year":"2018","journal-title":"J Pain Res"},{"key":"pone.0300081.ref061","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1002\/cne.21620","article-title":"Organization of pERK-immunoreactive cells in trigeminal spinal nucleus caudalis and upper cervical cord following capsaicin injection into oral and craniofacial regions in rats","volume":"507","author":"N Noma","year":"2008","journal-title":"J Comp Neurol"},{"key":"pone.0300081.ref062","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/0014-4886(86)90068-3","article-title":"Acute ipsilateral hyperalgesia and chronic contralateral hypoalgesia after unilateral 6-hydroxydopamine lesions of the substantia nigra","volume":"91","author":"RJ Carey","year":"1986","journal-title":"Exp Neurol"},{"key":"pone.0300081.ref063","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S0074-7742(08)60680-7","article-title":"Peptides and nociception","volume":"25","author":"D Luttinger","year":"1984","journal-title":"Int Rev Neurobiol"},{"key":"pone.0300081.ref064","doi-asserted-by":"crossref","first-page":"101S","DOI":"10.1111\/j.1469-445X.2000.tb00013.x","article-title":"Catecholaminergic mechanisms underlying neurohypophysial hormone responses to unconditioned or conditioned aversive stimuli in rats","volume":"85","author":"T. Onaka","year":"2000","journal-title":"Exp Physiol"},{"key":"pone.0300081.ref065","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1097\/00001756-200108080-00042","article-title":"Medullary A1 noradrenergic neurones may mediate oxytocin release after noxious stimuli","volume":"12","author":"T Onaka","year":"2001","journal-title":"NeuroReport"},{"key":"pone.0300081.ref066","doi-asserted-by":"crossref","first-page":"248","DOI":"10.3389\/fnmol.2018.00248","article-title":"Oxytocin relieves neuropathic pain through GABA release and presynaptic TRPV1 inhibition in spinal cord.","volume":"11","author":"WP Sun","year":"2018","journal-title":"Front Mol Neurosci."},{"key":"pone.0300081.ref067","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/BF00218970","article-title":"Identification of the vasopressin producing and of the oxytocin producing neurons in hypothalamic magnocellular neurosecretory-system of rat","volume":"164","author":"F Vandesande","year":"1975","journal-title":"Cell Tissue Res"},{"key":"pone.0300081.ref068","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/0168-0102(96)01029-2","article-title":"A selective role of brainstem noradrenergic neurons in oxytocin release from the neurohypophysis following noxious stimuli in the rat","volume":"25","author":"T Onaka","year":"1996","journal-title":"Neurosci Res"},{"key":"pone.0300081.ref069","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1744-8069-4-19","article-title":"Oxytocin-induced antinociception in the spinal cord is mediated by a subpopulation of glutamatergic neurons in lamina I-II which amplify GABAergic inhibition","volume":"4","author":"JD Breton","year":"2008","journal-title":"Mol Pain"},{"key":"pone.0300081.ref070","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.jphs.2018.04.002","article-title":"Neuropeptide oxytocin enhances Mu Opioid receptor signaling as a positive allosteric modulator","volume":"137","author":"Y Meguro","year":"2018","journal-title":"J Pharmacol Sci"},{"key":"pone.0300081.ref071","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1152\/jn.00609.2013","article-title":"Synaptic modulation and inward current produced by oxytocin in substantia gelatinosa neurons of adult rat spinal cord slices","volume":"111","author":"CY Jiang","year":"2014","journal-title":"J Neurophysiol"},{"key":"pone.0300081.ref072","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1097\/j.pain.0000000000000808","article-title":"Oxytocin alleviates orofacial mechanical hypersensitivity associated with infraorbital nerve injury through vasopressin-1A receptors of the rat trigeminal ganglia","volume":"158","author":"A Kubo","year":"2017","journal-title":"Pain"},{"key":"pone.0300081.ref073","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.neuropharm.2017.11.031","article-title":"Oxytocin inhibits the rat medullary dorsal horn Sp5c\/C1 nociceptive transmission through OT but not V1A receptors","volume":"129","author":"E Garc\u00eda-Boll","year":"2018","journal-title":"Neuropharmacology"},{"key":"pone.0300081.ref074","first-page":"1275","article-title":"Involvement of central opiate receptors in modulation of centrally administered oxytocin-induced antinociception.","volume":"21","author":"A Erfanparast","year":"2018","journal-title":"Iran J Basic Med Sci"},{"key":"pone.0300081.ref075","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.neuroscience.2017.09.041","article-title":"Oxytocin and pain perception: from animal models to human Research","volume":"387","author":"S Boll","year":"2018","journal-title":"Neuroscience"},{"key":"pone.0300081.ref076","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1097\/ALN.0000000000000539","article-title":"Phase 1 safety assessment of intrathecal oxytocin","volume":"122","author":"JC Eisenach","year":"2015","journal-title":"Anesthesiology"},{"key":"pone.0300081.ref077","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1136\/gut.39.5.741","article-title":"Oxytocin increases thresholds of colonic visceral perception in patients with irritable bowel syndrome","volume":"39","author":"D Louvel","year":"1996","journal-title":"Gut"},{"key":"pone.0300081.ref078","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1007\/s00296-014-2953-y","article-title":"Oxytocin nasal spray in fibromyalgic patients.","volume":"34","author":"S Mameli","year":"2014","journal-title":"Rheumatol Int"},{"key":"pone.0300081.ref079","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1097\/PSY.0000000000000068","article-title":"The effect of intranasal oxytocin administration on acute cold pressor pain: A placebo-controlled, double-blind, within-participants crossover investigation.","volume":"76","author":"JA Rash","year":"2014","journal-title":"Psychosom Med."},{"issue":"2","key":"pone.0300081.ref080","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1111\/head.13082","article-title":"Oxytocin and migraine headache.","volume":"57","author":"A Tzabazis","year":"2017","journal-title":"Headache."},{"key":"pone.0300081.ref081","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.npep.2012.12.003","article-title":"The interaction between the oxytocin and pain modulation in headache patients","volume":"47","author":"YL Wang","year":"2013","journal-title":"Neuropeptides"},{"key":"pone.0300081.ref082","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1097\/00007632-199404150-00001","article-title":"Intrathecal administration of oxytocin induces analgesia in low back pain involving the endogenous opiate peptide system","volume":"19","author":"J. Yang","year":"1994","journal-title":"Spine"},{"key":"pone.0300081.ref083","doi-asserted-by":"crossref","first-page":"31606","DOI":"10.1038\/srep31606","article-title":"Pain modulation by intranasal oxytocin and emotional picture viewing\u2014a randomized double-blind fMRI study","volume":"6","author":"M Zunhammer","year":"2016","journal-title":"Sci Rep"},{"key":"pone.0300081.ref084","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.regpep.2006.04.004","article-title":"Role of kappa- and delta-opioid receptors in the antinociceptive effect of oxytocin in formalin-induced pain response in mice","volume":"135","author":"Reeta Kh","year":"2006","journal-title":"Regul Pept"},{"key":"pone.0300081.ref085","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1016\/j.peptides.2007.03.003","article-title":"Central oxytocin enhances antinociception in the rat","volume":"28","author":"J Yang","year":"2007","journal-title":"Peptides"},{"key":"pone.0300081.ref086","doi-asserted-by":"crossref","first-page":"S45","DOI":"10.1016\/S0304-3959(99)00137-2","article-title":"Endogenous mechanisms of sensory modulation","author":"R Dubner","year":"1999","journal-title":"Pain"},{"key":"pone.0300081.ref087","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/S0014-4886(03)00346-7","article-title":"Role of micro-opioid receptors in formalin-induced pain behavior in mice","volume":"184","author":"CS Zhao","year":"2003","journal-title":"Exp Neurol"},{"key":"pone.0300081.ref088","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1152\/jn.00646.2020","article-title":"Activation of oxytocin receptor in the trigeminal ganglion attenuates orofacial ectopic pain attributed to inferior alveolar nerve injury","volume":"125","author":"CL Huang","year":"2021","journal-title":"J Neurophysiol"},{"key":"pone.0300081.ref089","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1152\/physrev.00031.2017","article-title":"The oxytocin receptor: from intracellular signaling to behavior","volume":"98","author":"B Jurek","year":"2018","journal-title":"Physiol Rev"},{"key":"pone.0300081.ref090","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1016\/j.peptides.2011.08.021","article-title":"Oxytocin in the rat caudate nucleus influences pain modulation","volume":"32","author":"J Yang","year":"2011","journal-title":"Peptides"},{"key":"pone.0300081.ref091","doi-asserted-by":"crossref","first-page":"109411","DOI":"10.1016\/j.celrep.2021.109411","article-title":"Oxytocin in the anterior cingulate cortex attenuates neuropathic pain and emotional anxiety by inhibiting presynaptic long-term potentiation","volume":"36","author":"XH Li","year":"2021","journal-title":"Cell Rep"},{"key":"pone.0300081.ref092","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1152\/physrev.2001.81.2.629","article-title":"The oxytocin receptor system: structure, function, and regulation","volume":"81","author":"G Gimpl","year":"2001","journal-title":"Physiol Rev"},{"key":"pone.0300081.ref093","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1515\/revneuro-2017-0068","article-title":"Role of central oxytocin and dopamine systems in nociception and their possible interactions: suggested hypotheses.","volume":"29","author":"M Gamal-Eltrabily","year":"2018","journal-title":"Rev Neurosci."},{"key":"pone.0300081.ref094","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/0014-2999(90)90497-T","article-title":"Effect of apomorphine on oxytocin concentrations in different brain areas and plasma of MALE-RATS","volume":"182","author":"MR Melis","year":"1990","journal-title":"Eur J 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