{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:25:51Z","timestamp":1760243151175,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2015,11,18]],"date-time":"2015-11-18T00:00:00Z","timestamp":1447804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["DFG, NI-705\/3-1","GRK 1172"],"award-info":[{"award-number":["DFG, NI-705\/3-1","GRK 1172"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Else Kr\u00f6ner-Fresenius Foundation","award":["TRIP"],"award-info":[{"award-number":["TRIP"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The processing of pain undergoes several changes in aging that affect sensory nociceptive fibers and the endogenous neuronal inhibitory systems. So far, it is not completely clear whether age-induced modifications are associated with an increase or decrease in pain perception. In this study, we assessed the impact of age on inflammatory nociception in mice and the role of the hormonal inhibitory systems in this context. We investigated the nociceptive behavior of 12-month-old versus 6\u20138-week-old mice in two behavioral models of inflammatory nociception. Levels of TRP channels, and cortisol as well as cortisol targets, were measured by qPCR, ELISA, and Western blot in the differently aged mice. We observed an age-related reduction in nociceptive behavior during inflammation as well as a higher level of cortisol in the spinal cord of aged mice compared to young mice, while TRP channels were not reduced. Among potential cortisol targets, the NF-\u03baB inhibitor protein alpha (I\u03baB\u03b1) was increased, which might contribute to inhibition of NF-\u03baB and a decreased expression and activity of the inducible nitric oxide synthase (iNOS). In conclusion, our results reveal a reduced nociceptive response in aged mice, which might be at least partially mediated by an augmented inflammation-induced increase in the hormonal inhibitory system involving cortisol.<\/jats:p>","DOI":"10.3390\/ijms161126041","type":"journal-article","created":{"date-parts":[[2015,11,18]],"date-time":"2015-11-18T10:35:12Z","timestamp":1447842912000},"page":"27508-27519","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Age-Dependent Changes in the Inflammatory Nociceptive Behavior of Mice"],"prefix":"10.3390","volume":"16","author":[{"given":"Tanya","family":"King-Himmelreich","sequence":"first","affiliation":[{"name":"<i>pharmazentrum frankfurt<\/i>\/ZAFES, Institut f\u00fcr Klinische Pharmakologie, Klinikum der Goethe-Universit\u00e4t Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"M\u00f6ser","sequence":"additional","affiliation":[{"name":"<i>pharmazentrum frankfurt<\/i>\/ZAFES, Institut f\u00fcr Klinische Pharmakologie, Klinikum der Goethe-Universit\u00e4t Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miriam","family":"Wolters","sequence":"additional","affiliation":[{"name":"<i>pharmazentrum frankfurt<\/i>\/ZAFES, Institut f\u00fcr Klinische Pharmakologie, Klinikum der Goethe-Universit\u00e4t Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrin","family":"Olbrich","sequence":"additional","affiliation":[{"name":"<i>pharmazentrum frankfurt<\/i>\/ZAFES, Institut f\u00fcr Klinische Pharmakologie, Klinikum der Goethe-Universit\u00e4t Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerd","family":"Geisslinger","sequence":"additional","affiliation":[{"name":"<i>pharmazentrum frankfurt<\/i>\/ZAFES, Institut f\u00fcr Klinische Pharmakologie, Klinikum der Goethe-Universit\u00e4t Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ellen","family":"Niederberger","sequence":"additional","affiliation":[{"name":"<i>pharmazentrum frankfurt<\/i>\/ZAFES, Institut f\u00fcr Klinische Pharmakologie, Klinikum der Goethe-Universit\u00e4t Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2015,11,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.neurobiolaging.2005.04.009","article-title":"Reduced thermal sensitivity and nav1.8 and trpv1 channel expression in sensory neurons of aged mice","volume":"27","author":"Wang","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1093\/geronj\/40.3.268","article-title":"Environmentally induced analgesia: An age-related decline in an endogenous opioid system","volume":"40","author":"Hamm","year":"1985","journal-title":"J. Gerontol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1037\/0882-7974.1.3.195","article-title":"Environmentally induced analgesia: Age-related decline in a neurally mediated, nonopioid system","volume":"1","author":"Hamm","year":"1986","journal-title":"Psychol. Aging"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1097\/00002508-200407000-00004","article-title":"A review of age differences in the neurophysiology of nociception and the perceptual experience of pain","volume":"20","author":"Gibson","year":"2004","journal-title":"Clin. J. Pain"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/S0149-7634(00)00041-5","article-title":"Age differences in nociception and pain behaviours in the rat","volume":"24","author":"Gagliese","year":"2000","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.neubiorev.2015.01.022","article-title":"Comparison of operant escape and reflex tests of nociceptive sensitivity","volume":"51","author":"Vierck","year":"2015","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.1016\/j.pain.2013.07.015","article-title":"Offset analgesia is reduced in older adults","volume":"154","author":"Naugle","year":"2013","journal-title":"Pain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.bbr.2015.04.014","article-title":"Age-related differences in conditioned pain modulation of sensitizing and desensitizing trends during response dependent stimulation","volume":"289","author":"Naugle","year":"2015","journal-title":"Behav. Brain Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1093\/bja\/aet077","article-title":"Dynamic output and control of the hypothalamic-pituitary-adrenal axis in critical illness and major surgery","volume":"111","author":"Gibbison","year":"2013","journal-title":"Br. J. Anaesth."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/0006-8993(83)90024-0","article-title":"Corticosterone receptors decline in a site-specific manner in the aged rat brain","volume":"289","author":"Sapolsky","year":"1983","journal-title":"Brain Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1126\/science.3014662","article-title":"Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones","volume":"233","author":"Besedovsky","year":"1986","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1128\/MCB.15.2.943","article-title":"Characterization of mechanisms involved in transrepression of nf-kappa b by activated glucocorticoid receptors","volume":"15","author":"Scheinman","year":"1995","journal-title":"Mol. Cell. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4698","DOI":"10.1093\/emboj\/16.15.4698","article-title":"I kappab alpha-independent downregulation of nf-kappab activity by glucocorticoid receptor","volume":"16","author":"Heck","year":"1997","journal-title":"EMBO J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1016\/j.bbadis.2007.03.003","article-title":"Trp channels and pain","volume":"1772","author":"Cortright","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6473","DOI":"10.1523\/JNEUROSCI.20-17-06473.2000","article-title":"Induction of ikappabalpha mrna expression in the brain by glucocorticoids: A negative feedback mechanism for immune-to-brain signaling","volume":"20","author":"Quan","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.neuroscience.2014.12.062","article-title":"Activation of nf-kappab signaling pathway in hsv-1-induced mouse facial palsy: Possible relation to therapeutic effect of glucocorticoids","volume":"289","author":"Liu","year":"2015","journal-title":"Neuroscience"},{"key":"ref_17","first-page":"G1290","article-title":"Dexamethasone suppresses inos gene expression by upregulating i-kappa b alpha and inhibiting nf-kappa b","volume":"273","author":"Taylor","year":"1997","journal-title":"Am. J. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1096\/fj.00-0716fje","article-title":"Celecoxib loses its anti-inflammatory efficacy at high doses through activation of nf-kappab","volume":"15","author":"Niederberger","year":"2001","journal-title":"FASEB J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/0531-5565(94)90039-6","article-title":"Effect of long-term acetyl-l-carnitine on stress-induced analgesia in the aging rat","volume":"29","author":"Ghirardi","year":"1994","journal-title":"Exp. Gerontol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1093\/geronj\/41.3.336","article-title":"Environmentally-induced analgesia: Age-related differences in a hormonally-mediated, nonopioid system","volume":"41","author":"Hamm","year":"1986","journal-title":"J. Gerontol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/S0163-1047(05)80064-0","article-title":"Multivariate analysis of behavioral aging highlights some unexpected features of complex systems organization","volume":"61","author":"Giuliani","year":"1994","journal-title":"Behav. Neural Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/0031-9384(86)90446-4","article-title":"Age-related decrements in the analgesic response to cold-water swims","volume":"36","author":"Kramer","year":"1986","journal-title":"Physiol. Behav."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"S27","DOI":"10.1111\/j.1526-4637.2011.01311.x","article-title":"The effects of age on pain sensitivity: Preclinical studies","volume":"13","author":"Yezierski","year":"2012","journal-title":"Pain Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"9792","DOI":"10.1007\/s11357-015-9792-y","article-title":"Development of monosodium acetate-induced osteoarthritis and inflammatory pain in ageing mice","volume":"37","author":"Ogbonna","year":"2015","journal-title":"Age (Dordr)"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/S0197-4580(99)00061-5","article-title":"Age differences in the response to the formalin test in rats","volume":"20","author":"Gagliese","year":"1999","journal-title":"Neurobiol. Aging"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1126\/science.270.5234.283","article-title":"Role of transcriptional activation of i kappa b alpha in mediation of immunosuppression by glucocorticoids","volume":"270","author":"Scheinman","year":"1995","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/S0361-9230(00)00275-6","article-title":"Inhibition of microglial cell activation by cortisol","volume":"52","author":"Drew","year":"2000","journal-title":"Brain Res. Bull."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1002\/1097-4547(20001115)62:4<503::AID-JNR4>3.0.CO;2-A","article-title":"Dehydroepiandrosterone inhibits microglial nitric oxide production in a stimulus-specific manner","volume":"62","author":"Barger","year":"2000","journal-title":"J. Neurosci. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.lfs.2003.10.042","article-title":"Inos-mediated nitric oxide production and its regulation","volume":"75","author":"Aktan","year":"2004","journal-title":"Life Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3976","DOI":"10.4049\/jimmunol.159.8.3976","article-title":"In vivo inhibition of nuclear factor-kappa b activation prevents inducible nitric oxide synthase expression and systemic hypotension in a rat model of septic shock","volume":"159","author":"Liu","year":"1997","journal-title":"J. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.brainres.2006.10.050","article-title":"Gabrb3 gene deficient mice exhibit increased risk assessment behavior, hypotonia and expansion of the plexus of locus coeruleus dendrites","volume":"1129","author":"Hashemi","year":"2007","journal-title":"Brain Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"174","DOI":"10.3389\/fnbeh.2013.00174","article-title":"Learning and memory with neuropathic pain: Impact of old age and progranulin deficiency","volume":"7","author":"Albuquerque","year":"2013","journal-title":"Front. Behav. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/0304-3959(88)90026-7","article-title":"A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia","volume":"32","author":"Hargreaves","year":"1988","journal-title":"Pain"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/S0022-3565(25)05180-8","article-title":"Synthetic analgesics. Ii. Dithienylbutenyl- and dithienylbutylamines","volume":"107","author":"Eddy","year":"1953","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/S0304-3959(98)00197-3","article-title":"Heritability of nociception i: Responses of 11 inbred mouse strains on 12 measures of nociception","volume":"80","author":"Mogil","year":"1999","journal-title":"Pain"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/0304-3959(77)90130-0","article-title":"The formalin test: A quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats","volume":"4","author":"Dubuisson","year":"1977","journal-title":"Pain"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S1090-3801(97)90052-5","article-title":"Intraplantar zymosan as a reliable, quantifiable model of thermal and mechanical hyperalgesia in the rat","volume":"1","author":"Meller","year":"1997","journal-title":"Eur. J. Pain"},{"key":"ref_38","first-page":"532","article-title":"A reagent for the single-step simultaneous isolation of RNA, DNA and proteins from cell and tissue samples","volume":"15","author":"Chomczynski","year":"1993","journal-title":"Biotechniques"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/0003-2697(82)90118-X","article-title":"Analysis of nitrate, nitrite, and [15n]nitrate in biological fluids","volume":"126","author":"Green","year":"1982","journal-title":"Anal. Biochem."},{"key":"ref_40","first-page":"1265","article-title":"Glucocorticoid dose dependent downregulation of glucocorticoid receptors in patients with rheumatic diseases","volume":"27","author":"Sanden","year":"2000","journal-title":"J. Rheumatol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/16\/11\/26041\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:52:17Z","timestamp":1760215937000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/16\/11\/26041"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,11,18]]},"references-count":40,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2015,11]]}},"alternative-id":["ijms161126041"],"URL":"https:\/\/doi.org\/10.3390\/ijms161126041","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2015,11,18]]}}}