{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T14:51:50Z","timestamp":1769957510611,"version":"3.49.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T00:00:00Z","timestamp":1657152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Integr. Neurosci."],"abstract":"<jats:p>Varicella zoster virus (VZV) induces orofacial pain and female rats show greater pain than male rats. During the proestrus phase of the estrous cycle the VZV induce pain response is attenuated in female rats. A screen of gene expression changes in diestrus and proestrus female rats indicated neurexin 3\u03b1 (Nrxn3\u03b1) was elevated in the central amygdala of proestrus rats vs. diestrus rats. GABAergic neurons descend from the central amygdala to the lateral parabrachial region and Nrxn3\u03b1 is important for presynaptic \u03b3-Aminobutyric acid (GABA) release. Thus, we hypothesized that the reduced orofacial pain in male rats and proestrus female rats is the result of increased Nrxn3\u03b1 within the central amygdala that increases GABA release from axon terminals within the parabrachial and inhibits ascending pain signals. To test this hypothesis Nrxn3 \u03b1 expression was knocked-down by infusing shRNA constructs in the central amygdala. Then GABA release in the parabrachial was quantitated concomitant with measuring the pain response. Results revealed that knockdown of Nrxn3\u03b1 expression significantly increases the pain response in both male rats and proestrus female rats vs. diestrus rats. GABA release was significantly reduced in the parabrachial of male and proestrus female rats after Nrxn3\u03b1 knockdown. Neuronal activity of excitatory neurons was significantly inhibited in the parabrachial after Nrxn3\u03b1 knockdown. These results are consistent with the idea that Nrxn3 within the central amygdala controls VZV associated pain by regulating GABA release in the lateral parabrachial that then modulates ascending orofacial pain signals.<\/jats:p>","DOI":"10.3389\/fnint.2022.915797","type":"journal-article","created":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T15:13:56Z","timestamp":1657206836000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Sex Differences in the Role of Neurexin 3\u03b1 in Zoster Associated Pain"],"prefix":"10.3389","volume":"16","author":[{"given":"Phillip R.","family":"Kramer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikhail","family":"Umorin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Hornung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Douglas","family":"Benson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul R.","family":"Kinchington","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1002\/hipo.20703","article-title":"Aging alters the expression of genes for neuroprotection and synaptic function following acute estradiol treatment.","volume":"20","author":"Aenlle","year":"2010","journal-title":"Hippocampus"},{"key":"B2","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1038\/nn.4037","article-title":"Distinct circuit-dependent functions of presynaptic neurexin-3 at GABAergic and glutamatergic synapses.","volume":"18","author":"Aoto","year":"2015","journal-title":"Nat. Neurosci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"22","DOI":"10.3344\/kjp.2022.35.1.22","article-title":"The role of basolateral amygdala orexin 1 receptors on the modulation of pain and psychosocial deficits in nitroglycerin-induced migraine model in adult male rats.","volume":"35","author":"Askari-Zahabi","year":"2022","journal-title":"Korean J. Pain"},{"key":"B4","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.brainres.2010.11.008","article-title":"Pregabalin attenuates place escape\/avoidance behavior in a rat model of spinal cord injury.","volume":"1370","author":"Baastrup","year":"2011","journal-title":"Brain Res."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110098","article-title":"Neurexin-3 defines synapse- and sex-dependent diversity of GABAergic inhibition in ventral subiculum.","volume":"37","author":"Boxer","year":"2021","journal-title":"Cell Rep."},{"key":"B6","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/j.brainresrev.2004.07.008","article-title":"Allodynia in rats infected with varicella zoster virus\u2013a small animal model for post-herpetic neuralgia.","volume":"46","author":"Dalziel","year":"2004","journal-title":"Brain Res. Brain Res. Rev."},{"key":"B7","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1177\/0022034511411300","article-title":"The role of sensory fiber demography in trigeminal and postherpetic neuralgias.","volume":"91","author":"DaSilva","year":"2012","journal-title":"J. Dent. Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1016\/j.neuroscience.2007.01.051","article-title":"Sex-related differences in NMDA-evoked rat masseter muscle afferent discharge result from estrogen-mediated modulation of peripheral NMDA receptor activity.","volume":"146","author":"Dong","year":"2007","journal-title":"Neuroscience"},{"key":"B9","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1016\/j.neuron.2014.04.042","article-title":"Amygdala microcircuits controlling learned fear.","volume":"82","author":"Duvarci","year":"2014","journal-title":"Neuron"},{"key":"B10","doi-asserted-by":"publisher","first-page":"89","DOI":"10.3109\/07367228509144579","article-title":"The dorsomedial portion of trigeminal nucleus oralis (Vo) in the rat: cytology and projections to the cerebellum.","volume":"3","author":"Falls","year":"1985","journal-title":"Somatosens. Res."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1585","DOI":"10.1152\/jn.00269.2004","article-title":"Estrogen and inflammation increase the excitability of rat temporomandibular joint afferent neurons.","volume":"93","author":"Flake","year":"2005","journal-title":"J. Neurophysiol."},{"key":"B12","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.1099\/0022-1317-80-9-2433","article-title":"Behavioural changes in the rat following infection with varicella-zoster virus.","author":"Fleetwood-Walker","year":"1999","journal-title":"J. Gen. Virol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"11","DOI":"10.2174\/1876386300902010011","article-title":"c-Fos and pERK, which is a better marker for neuronal activation and central sensitization after noxious stimulation and tissue injury?","volume":"2","author":"Gao","year":"2009","journal-title":"Open. Pain J."},{"key":"B14","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.virol.2015.03.046","article-title":"Neuronal changes induced by varicella zoster virus in a rat model of postherpetic neuralgia.","volume":"482","author":"Guedon","year":"2015","journal-title":"Virology"},{"key":"B15","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1038\/gt.2014.43","article-title":"Relief of pain induced by varicella-zoster virus in a rat model of post-herpetic neuralgia using a herpes simplex virus vector expressing enkephalin.","volume":"21","author":"Guedon","year":"2014","journal-title":"Gene Ther."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1495","DOI":"10.1016\/j.neuroscience.2006.11.029","article-title":"Further characterization of a rat model of varicella zoster virus-associated pain: relationship between mechanical hypersensitivity and anxiety-related behavior, and the influence of analgesic drugs.","volume":"144","author":"Hasnie","year":"2007","journal-title":"Neuroscience"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21165749","article-title":"Comparing gene expression in the parabrachial and amygdala of diestrus and proestrus female rats after orofacial varicella zoster injection.","volume":"21","author":"Hornung","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1006\/viro.2001.1173","article-title":"Varicella-zoster virus gene expression in latently infected rat dorsal root ganglia.","volume":"289","author":"Kennedy","year":"2001","journal-title":"Virology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1016\/j.ijom.2004.08.010","article-title":"Specificity of meal pattern analysis as an animal model of dermining temporomandibular joint inflammation\/pain.","volume":"34","author":"Kerins","year":"2005","journal-title":"Int. J. Oral Maxiollofac. Surg."},{"key":"B20","doi-asserted-by":"publisher","first-page":"3680","DOI":"10.1210\/en.2008-1707","article-title":"The effects of cycling levels of 17beta-estradiol and progesterone on the magnitude of temporomandibular joint-induced nociception.","volume":"150","author":"Kramer","year":"2009","journal-title":"Endocrinology"},{"key":"B21","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.neuroscience.2017.05.030","article-title":"Lateral thalamic control of nociceptive response after whisker pad injection of varicella zoster virus.","volume":"356","author":"Kramer","year":"2017","journal-title":"Neuroscience"},{"key":"B22","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1006\/exnr.2000.7395","article-title":"A behavioral test paradigm to measure the aversive quality of inflammatory and neuropathic pain in rats.","volume":"163","author":"LaBuda","year":"2000","journal-title":"Exp. Neurol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.pain.2003.06.001","article-title":"Changes in temporomandibular pain and other symptoms across the menstrual cycle.","volume":"106","author":"LeResche","year":"2003","journal-title":"Pain"},{"key":"B24","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1016\/j.cell.2015.07.014","article-title":"Intact-brain analyses reveal distinct information carried by SNc dopamine subcircuits.","volume":"162","author":"Lerner","year":"2015","journal-title":"Cell"},{"key":"B25","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1038\/s41592-019-0471-2","article-title":"A genetically encoded fluorescent sensor for in vivo imaging of GABA.","volume":"16","author":"Marvin","year":"2019","journal-title":"Nat. Methods"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1590\/1414-431x20209950","article-title":"Temporomandibular inflammation mobilizes parvalbumin and FosB\/deltaFosB neurons of amygdala and dorsal raphe.","volume":"53","author":"Nascimento","year":"2020","journal-title":"Braz. J. Med. Biol. Res."},{"key":"B27","doi-asserted-by":"crossref","first-page":"S50","DOI":"10.1212\/WNL.45.12_Suppl_8.S50","article-title":"Herpes zoster ophthalmicus.","volume":"45","author":"Pavan-Langston","year":"1995","journal-title":"Neurology"},{"key":"B28","doi-asserted-by":"crossref","first-page":"10514","DOI":"10.1128\/JVI.73.12.10514-10518.1999","article-title":"Quantitation of latent varicella-zoster virus and herpes simplex virus genomes in human trigeminal ganglia.","volume":"73","author":"Pevenstein","year":"1999","journal-title":"J. Virol."},{"key":"B29","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1097\/00005792-198209000-00003","article-title":"Population-based study of herpes zoster and its sequelae.","volume":"61","author":"Ragozzino","year":"1982","journal-title":"Medicine"},{"key":"B30","doi-asserted-by":"publisher","first-page":"3424","DOI":"10.1523\/jneurosci.0075-20.2020","article-title":"An amygdalo-parabrachial pathway regulates pain perception and chronic pain.","volume":"40","author":"Raver","year":"2020","journal-title":"J. Neurosci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1734","DOI":"10.1038\/s41593-017-0012-1","article-title":"A craniofacial-specific monosynaptic circuit enables heightened affective pain.","volume":"20","author":"Rodriguez","year":"2017","journal-title":"Nat. Neurosci."},{"key":"B32","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1002\/cne.1054","article-title":"Distribution of estrogen receptor beta immunoreactivity in the rat central nervous system.","volume":"436","author":"Shughrue","year":"2001","journal-title":"J. Comp. Neurol."},{"key":"B33","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1002\/(SICI)1096-9861(19971201)388:4<507::AID-CNE1>3.0.CO;2-6","article-title":"Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system.","volume":"388","author":"Shughrue","year":"1997","journal-title":"J. Comp. Neurol."},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1186\/s12883-017-0882-6","article-title":"Sex differences underlying orofacial varicella zoster associated pain in rats.","volume":"17","author":"Stinson","year":"2017","journal-title":"BMC Neurol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1097\/00004728-200105000-00023","article-title":"Temporomandibular disorders: MR assessment of inflammatory changes in the posterior disk attachment during the menstrual cycle.","volume":"25","author":"Suenaga","year":"2001","journal-title":"J. Comput. Assist. Tomogr."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2065","DOI":"10.1111\/j.1460-9568.2008.06488.x","article-title":"Morphine modulation of temporomandibular joint-responsive units in superficial laminae at the spinomedullary junction in female rats depends on estrogen status.","volume":"28","author":"Tashiro","year":"2008","journal-title":"Eur. J. Neurosci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"3242","DOI":"10.1152\/jn.00677.2007","article-title":"Differential effects of estradiol on encoding properties of TMJ units in laminae I and V at the spinomedullary junction in female rats.","volume":"98","author":"Tashiro","year":"2007","journal-title":"J. Neurophysiol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.brainres.2006.02.008","article-title":"Estrogen alters c-Fos response to immobilization stress in the brain of ovariectomized rats.","volume":"1084","author":"Ueyama","year":"2006","journal-title":"Brain Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1523\/jneurosci.22-01-00142.2002","article-title":"Identification of the differentiation-associated Na+\/PI transporter as a novel vesicular glutamate transporter expressed in a distinct set of glutamatergic synapses.","volume":"22","author":"Varoqui","year":"2002","journal-title":"J. Neurosci."},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009689","article-title":"Varicella-zoster virus early infection but not complete replication is required for the induction of chronic hypersensitivity in rat models of postherpetic neuralgia.","volume":"17","author":"Warner","year":"2021","journal-title":"PLoS Pathog."}],"container-title":["Frontiers in Integrative Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnint.2022.915797\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T15:14:04Z","timestamp":1657206844000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnint.2022.915797\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,7]]},"references-count":40,"alternative-id":["10.3389\/fnint.2022.915797"],"URL":"https:\/\/doi.org\/10.3389\/fnint.2022.915797","relation":{},"ISSN":["1662-5145"],"issn-type":[{"value":"1662-5145","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,7]]},"article-number":"915797"}}