{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T18:23:01Z","timestamp":1793211781323,"version":"4.5.0"},"reference-count":122,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,2,1]],"date-time":"2021-02-01T00:00:00Z","timestamp":1612137600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,2,1]],"date-time":"2021-02-01T00:00:00Z","timestamp":1612137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute","award":["UO1 HL117664"],"award-info":[{"award-number":["UO1 HL117664"]}]},{"name":"U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute","award":["RO1 HL147562"],"award-info":[{"award-number":["RO1 HL147562"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Treatment of severe chronic and acute pain in sickle cell disease (SCD) remains challenging due to the interdependence of pain and psychosocial modulation. We examined whether modulation of the descending pain pathway through an enriched diet and companionship could alleviate pain in transgenic sickle mice. Mechanical and thermal hyperalgesia were reduced significantly with enriched diet and\/or companionship. Upon withdrawal of both conditions, analgesic effects observed prior to withdrawal were diminished. Serotonin (5-hydroxytryptamine, 5-HT) was found to be increased in the spinal cords of mice provided both treatments. Additionally, 5-HT production improved at the rostral ventromedial medulla and 5-HT accumulated at the dorsal horn of the spinal cord of sickle mice, suggesting the involvement of the descending pain pathway in the analgesic response. Modulation of 5-HT and its effect on hyperalgesia was also investigated through pharmaceutical approaches. Duloxetine, a serotonin-norepinephrine reuptake inhibitor, showed a similar anti-nociceptive effect as the combination of diet and companionship. Depletion of 5-HT through p-chlorophenylalanine attenuated the anti-hyperalgesic effect of enriched diet and companionship. More significantly, improved diet and companionship enhanced the efficacy of a sub-optimal dose of morphine for analgesia in sickle mice. These findings offer the potential to reduce opioid use without pharmacological interventions to develop effective pain management strategies.<\/jats:p>","DOI":"10.1038\/s41598-021-81654-1","type":"journal-article","created":{"date-parts":[[2021,2,1]],"date-time":"2021-02-01T11:06:44Z","timestamp":1612177604000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Diet and companionship modulate pain via a serotonergic mechanism"],"prefix":"10.1038","volume":"11","author":[{"given":"Huy","family":"Tran","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varun","family":"Sagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarita","family":"Jarrett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise F.","family":"Palzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajendra D.","family":"Badgaiyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalpna","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,1]]},"reference":[{"key":"81654_CR1","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/j.pain.2007.08.013","volume":"136","author":"D Bouhassira","year":"2008","unstructured":"Bouhassira, D., Lant\u00e9ri-Minet, M., Attal, N., Laurent, B. & Touboul, C. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 136, 380\u2013387 (2008).","journal-title":"Pain"},{"key":"81654_CR2","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.ejpain.2005.06.009","volume":"10","author":"H Breivik","year":"2006","unstructured":"Breivik, H., Collett, B., Ventafridda, V., Cohen, R. & Gallacher, D. Survey of chronic pain in Europe: Prevalence, impact on daily life, and treatment. Eur. J. Pain 10, 287\u2013287 (2006).","journal-title":"Eur. J. Pain"},{"key":"81654_CR3","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1007\/s10620-017-4488-z","volume":"62","author":"AI Koulouris","year":"2017","unstructured":"Koulouris, A. I., Banim, P. & Hart, A. R. Pain in patients with pancreatic cancer: Prevalence, mechanisms, management and future developments. Dig. Dis. Sci. 62, 861\u2013870 (2017).","journal-title":"Dig. Dis. Sci."},{"key":"81654_CR4","doi-asserted-by":"publisher","first-page":"E51","DOI":"10.1111\/papr.12132","volume":"14","author":"GP Dureja","year":"2014","unstructured":"Dureja, G. P. et al. Prevalence of chronic pain, impact on daily life, and treatment practices in India. Pain Pract. Off. J. World Inst. Pain 14, E51\u2013E62 (2014).","journal-title":"Pain Pract. Off. J. World Inst. Pain"},{"key":"81654_CR5","doi-asserted-by":"publisher","first-page":"T70","DOI":"10.1016\/j.jpain.2016.01.001","volume":"17","author":"RR Edwards","year":"2016","unstructured":"Edwards, R. R., Dworkin, R. H., Sullivan, M. D., Turk, D. & Wasan, A. D. The role of psychosocial processes in the development and maintenance of chronic pain disorders. J. Pain Off. J. Am. Pain Soc. 17, T70\u2013T92 (2016).","journal-title":"J. Pain Off. J. Am. Pain Soc."},{"key":"81654_CR6","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1037\/a0013628","volume":"16","author":"A Rosenblum","year":"2008","unstructured":"Rosenblum, A., Marsch, L. A., Joseph, H. & Portenoy, R. K. Opioids and the treatment of chronic pain: Controversies, current status, and future directions. Exp. Clin. Psychopharmacol. 16, 405\u2013416 (2008).","journal-title":"Exp. Clin. Psychopharmacol."},{"key":"81654_CR7","doi-asserted-by":"publisher","first-page":"1981","DOI":"10.1056\/NEJMp1011512","volume":"363","author":"S Okie","year":"2010","unstructured":"Okie, S. A flood of opioids, a rising tide of deaths. N. Engl. J. Med. 363, 1981\u20131985 (2010).","journal-title":"N. Engl. J. Med."},{"key":"81654_CR8","doi-asserted-by":"publisher","first-page":"540154","DOI":"10.1155\/2015\/540154","volume":"2015","author":"M Gupta","year":"2015","unstructured":"Gupta, M., Msambichaka, L., Ballas, S. K. & Gupta, K. Morphine for the treatment of pain in sickle cell disease. Sci. World J. 2015, 540154 (2015).","journal-title":"Sci. World J."},{"key":"81654_CR9","doi-asserted-by":"publisher","first-page":"2377","DOI":"10.1182\/blood-2017-05-782003","volume":"130","author":"H Tran","year":"2017","unstructured":"Tran, H., Gupta, M. & Gupta, K. Targeting novel mechanisms of pain in sickle cell disease. Blood 130, 2377\u20132385 (2017).","journal-title":"Blood"},{"key":"81654_CR10","doi-asserted-by":"publisher","first-page":"E500","DOI":"10.1503\/cmaj.171286","volume":"190","author":"R Daoust","year":"2018","unstructured":"Daoust, R. et al. Recent opioid use and fall-related injury among older patients with trauma. CMAJ 190, E500\u2013E506 (2018).","journal-title":"CMAJ"},{"key":"81654_CR11","doi-asserted-by":"publisher","first-page":"1444","DOI":"10.1001\/jama.2018.0158","volume":"319","author":"AH Mokdad","year":"2018","unstructured":"Mokdad, A. H. et al. The state of US Health, 1990\u20132016: Burden of diseases, injuries, and risk factors among US states. JAMA 319, 1444\u20131472 (2018).","journal-title":"JAMA"},{"key":"81654_CR12","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1208\/s12248-010-9196-y","volume":"12","author":"LS Premkumar","year":"2010","unstructured":"Premkumar, L. S. Targeting TRPV1 as an alternative approach to narcotic analgesics to treat chronic pain conditions. AAPS J. 12, 361\u2013370 (2010).","journal-title":"AAPS J."},{"key":"81654_CR13","doi-asserted-by":"publisher","first-page":"3753","DOI":"10.1172\/JCI43195","volume":"120","author":"G Burgess","year":"2010","unstructured":"Burgess, G. & Williams, D. The discovery and development of analgesics: New mechanisms, new modalities. J. Clin. Invest. 120, 3753\u20133759 (2010).","journal-title":"J. Clin. Invest."},{"issue":"Suppl 1","key":"81654_CR14","doi-asserted-by":"publisher","first-page":"S43","DOI":"10.1097\/j.pain.0000000000000798","volume":"158","author":"F Porreca","year":"2017","unstructured":"Porreca, F. & Navratilova, E. Reward, motivation, and emotion of pain and its relief. Pain 158(Suppl 1), S43\u2013S49 (2017).","journal-title":"Pain"},{"key":"81654_CR15","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1016\/j.mcna.2017.04.012","volume":"101","author":"RA Bonakdar","year":"2017","unstructured":"Bonakdar, R. A. Integrative pain management. Med. Clin. N. Am. 101, 987\u20131004 (2017).","journal-title":"Med. Clin. N. Am."},{"key":"81654_CR16","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1037\/0022-006X.57.6.725","volume":"57","author":"KM Gil","year":"1989","unstructured":"Gil, K. M., Abrams, M. R., Phillips, G. & Keefe, F. J. Sickle cell disease pain: Relation of coping strategies to adjustment. J. Consult. Clin. Psychol. 57, 725\u2013731 (1989).","journal-title":"J. Consult. Clin. Psychol."},{"issue":"33","key":"81654_CR17","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1016\/0277-9536(91)90385-P","volume":"1982","author":"TA Revenson","year":"1991","unstructured":"Revenson, T. A., Schiaffino, K. M., Majerovitz, S. D. & Gibofsky, A. Social support as a double-edged sword: the relation of positive and problematic support to depression among rheumatoid arthritis patients. Soc. Sci. Med. 1982(33), 807\u2013813 (1991).","journal-title":"Soc. Sci. Med."},{"key":"81654_CR18","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.jpain.2017.08.010","volume":"5","author":"PH Finan","year":"2017","unstructured":"Finan, P. H. et al. Daily opioid use fluctuates as a function of pain, catastrophizing, and affect in patients with sickle cell disease: An electronic daily diary analysis. J. Pain Off. J. Am. Pain Soc. 5, 5\u20136. https:\/\/doi.org\/10.1016\/j.jpain.2017.08.010 (2017).","journal-title":"J. Pain Off. J. Am. Pain Soc."},{"key":"81654_CR19","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1111\/bjc.12078","volume":"54","author":"ALJ Burke","year":"2015","unstructured":"Burke, A. L. J., Mathias, J. L. & Denson, L. A. Psychological functioning of people living with chronic pain: A meta-analytic review. Br. J. Clin. Psychol. 54, 345\u2013360 (2015).","journal-title":"Br. J. Clin. Psychol."},{"key":"81654_CR20","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1097\/01.PSY.0000030388.62434.46","volume":"65","author":"JL Brown","year":"2003","unstructured":"Brown, J. L., Sheffield, D., Leary, M. R. & Robinson, M. E. Social support and experimental pain. Psychosom. Med. 65, 276\u2013283 (2003).","journal-title":"Psychosom. Med."},{"key":"81654_CR21","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1080\/13548509808402233","volume":"3","author":"A Harris","year":"1998","unstructured":"Harris, A., Parker, N. & Barker, C. Adults with sickle cell disease: Psychological impact and experience of hospital services. Psychol. Health Med. 3, 171\u2013179 (1998).","journal-title":"Psychol. Health Med."},{"key":"81654_CR22","doi-asserted-by":"publisher","first-page":"e69460","DOI":"10.1371\/journal.pone.0069460","volume":"8","author":"B Crettaz","year":"2013","unstructured":"Crettaz, B. et al. Stress-induced allodynia\u2013evidence of increased pain sensitivity in healthy humans and patients with chronic pain after experimentally induced psychosocial stress. PLoS ONE 8, e69460 (2013).","journal-title":"PLoS ONE"},{"key":"81654_CR23","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.jpain.2012.10.016","volume":"14","author":"S Bruehl","year":"2013","unstructured":"Bruehl, S. et al. Personalized medicine and opioid analgesic prescribing for chronic pain: Opportunities and challenges. J. Pain Off. J. Am. Pain Soc. 14, 103\u2013113 (2013).","journal-title":"J. Pain Off. J. Am. Pain Soc."},{"key":"81654_CR24","doi-asserted-by":"publisher","first-page":"S42","DOI":"10.4065\/mcp.2009.0648","volume":"85","author":"DC Turk","year":"2010","unstructured":"Turk, D. C., Audette, J., Levy, R. M., Mackey, S. C. & Stanos, S. Assessment and treatment of psychosocial comorbidities in patients with neuropathic pain. Mayo Clin. Proc. 85, S42\u2013S50 (2010).","journal-title":"Mayo Clin. Proc."},{"key":"81654_CR25","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1542\/peds.64.4.533","volume":"64","author":"L Zeltzer","year":"1979","unstructured":"Zeltzer, L., Dash, J. & Holland, J. P. Hypnotically induced pain control in sickle cell anemia. Pediatrics 64, 533\u2013536 (1979).","journal-title":"Pediatrics"},{"key":"81654_CR26","doi-asserted-by":"publisher","first-page":"1635","DOI":"10.2147\/JPR.S131859","volume":"10","author":"RR Bhatt","year":"2017","unstructured":"Bhatt, R. R. et al. The effect of hypnosis on pain and peripheral blood flow in sickle-cell disease: A pilot study. J. Pain Res. 10, 1635\u20131644 (2017).","journal-title":"J. Pain Res."},{"key":"81654_CR27","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.pain.2006.12.013","volume":"131","author":"LM McCracken","year":"2007","unstructured":"McCracken, L. M., Gauntlett-Gilbert, J. & Vowles, K. E. The role of mindfulness in a contextual cognitive-behavioral analysis of chronic pain-related suffering and disability. Pain 131, 63\u201369 (2007).","journal-title":"Pain"},{"key":"81654_CR28","doi-asserted-by":"publisher","first-page":"3647","DOI":"10.1182\/blood-2012-04-383430","volume":"120","author":"SK Ballas","year":"2012","unstructured":"Ballas, S. K., Gupta, K. & Adams-Graves, P. Sickle cell pain: A critical reappraisal. Blood 120, 3647\u20133656 (2012).","journal-title":"Blood"},{"key":"81654_CR29","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.pain.2009.07.008","volume":"146","author":"WR Smith","year":"2009","unstructured":"Smith, W. R. et al. Climatic and geographic temporal patterns of pain in the Multicenter Study of Hydroxyurea. Pain 146, 91\u201398 (2009).","journal-title":"Pain"},{"key":"81654_CR30","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1038\/ncomms1104","volume":"1","author":"FB Piel","year":"2010","unstructured":"Piel, F. B. et al. Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis. Nat. Commun. 1, 104 (2010).","journal-title":"Nat. Commun."},{"key":"81654_CR31","doi-asserted-by":"publisher","first-page":"S512","DOI":"10.1016\/j.amepre.2009.12.022","volume":"38","author":"KL Hassell","year":"2010","unstructured":"Hassell, K. L. Population estimates of sickle cell disease in the U.S. Am. J. Prev. Med. 38, S512\u2013S521 (2010).","journal-title":"Am. J. Prev. Med."},{"key":"81654_CR32","unstructured":"Bediako, S. M. Psychosocial aspects of sickle cell disease: A primer for African American psychologists. in Handbook of African American Psychology. 417\u2013427 (Sage, Loondon, 2009)."},{"key":"81654_CR33","first-page":"1301571","volume":"33","author":"K Martinowich","year":"2007","unstructured":"Martinowich, K. & Lu, B. Interaction between BDNF and Serotonin: Role in mood disorders. Neuropsychopharmacology 33, 1301571 (2007).","journal-title":"Neuropsychopharmacology"},{"key":"81654_CR34","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.brainresrev.2007.07.014","volume":"56","author":"A Alcaro","year":"2007","unstructured":"Alcaro, A., Huber, R. & Panksepp, J. Behavioral functions of the mesolimbic dopaminergic system: An affective neuroethological perspective. Brain Res. Rev. 56, 283\u2013321 (2007).","journal-title":"Brain Res. Rev."},{"key":"81654_CR35","doi-asserted-by":"publisher","first-page":"66","DOI":"10.3389\/fnmol.2014.00024","volume":"7","author":"JA Bravo","year":"2014","unstructured":"Bravo, J. A., Dinan, T. G. & Cryan, J. F. Early-life stress induces persistent alterations in 5-HT1A receptor and serotonin transporter mRNA expression in the adult rat brain. Front. Mol. Neurosci. 7, 66 (2014).","journal-title":"Front. Mol. Neurosci."},{"key":"81654_CR36","doi-asserted-by":"publisher","first-page":"3779","DOI":"10.1172\/JCI43766","volume":"120","author":"MH Ossipov","year":"2010","unstructured":"Ossipov, M. H., Dussor, G. O. & Porreca, F. Central modulation of pain. J. Clin. Invest. 120, 3779\u20133787 (2010).","journal-title":"J. Clin. Invest."},{"key":"81654_CR37","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/S0301-0082(02)00009-6","volume":"66","author":"MJ Millan","year":"2002","unstructured":"Millan, M. J. Descending control of pain. Prog. Neurobiol. 66, 355\u2013474 (2002).","journal-title":"Prog. Neurobiol."},{"key":"81654_CR38","doi-asserted-by":"publisher","unstructured":"Lader, M. Generalized Anxiety Disorder. in Encyclopedia of Psychopharmacology 699\u2013702 (Springer, Berlin, 2015). https:\/\/doi.org\/10.1007\/978-3-642-36172-2_317.","DOI":"10.1007\/978-3-642-36172-2_317"},{"key":"81654_CR39","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.jad.2008.03.009","volume":"111","author":"CM Sonnenberg","year":"2008","unstructured":"Sonnenberg, C. M., Deeg, D. J. H., Comijs, H. C., van Tilburg, W. & Beekman, A. T. F. Trends in antidepressant use in the older population: Results from the LASA-study over a period of 10 years. J. Affect. Disord. 111, 299\u2013305 (2008).","journal-title":"J. Affect. Disord."},{"key":"81654_CR40","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1038\/sj.mp.4001949","volume":"12","author":"HG Ruh\u00e9","year":"2007","unstructured":"Ruh\u00e9, H. G., Mason, N. S. & Schene, A. H. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: A meta-analysis of monoamine depletion studies. Mol. Psychiatry 12, 331\u2013359 (2007).","journal-title":"Mol. Psychiatry"},{"key":"81654_CR41","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1016\/S0091-3057(01)00670-0","volume":"71","author":"SN Young","year":"2002","unstructured":"Young, S. N. & Leyton, M. The role of serotonin in human mood and social interaction: Insight from altered tryptophan levels. Pharmacol. Biochem. Behav. 71, 857\u2013865 (2002).","journal-title":"Pharmacol. Biochem. Behav."},{"key":"81654_CR42","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1007\/BF00401382","volume":"10","author":"SS Tenen","year":"1967","unstructured":"Tenen, S. S. The effects of p-chlorophenylalanine, a serotonin depletor, on avoidance acquisition, pain sensitivity and related behavior in the rat. Psychopharmacologia 10, 204\u2013219 (1967).","journal-title":"Psychopharmacologia"},{"key":"81654_CR43","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1007\/BF00401407","volume":"12","author":"SS Tenen","year":"1968","unstructured":"Tenen, S. S. Antagonism of the analgesic effect of morphine and other drugs by p-chlorophenylalanine, a serotonin depletor. Psychopharmacologia 12, 278\u2013285 (1968).","journal-title":"Psychopharmacologia"},{"key":"81654_CR44","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1111\/j.1600-0447.2005.00540.x","volume":"111","author":"RA Bressan","year":"2005","unstructured":"Bressan, R. A. & Crippa, J. A. The role of dopamine in reward and pleasure behaviour\u2014Review of data from preclinical research. Acta Psychiatr. Scand. 111, 14\u201321 (2005).","journal-title":"Acta Psychiatr. Scand."},{"key":"81654_CR45","first-page":"315","volume":"32","author":"RJ Wurtman","year":"1980","unstructured":"Wurtman, R. J., Hefti, F. & Melamed, E. Precursor control of neurotransmitter synthesis. Pharmacol. Rev. 32, 315\u2013335 (1980).","journal-title":"Pharmacol. Rev."},{"key":"81654_CR46","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1007\/s00213-008-1254-0","volume":"201","author":"CR Markus","year":"2008","unstructured":"Markus, C. R., Firk, C., Gerhardt, C., Kloek, J. & Smolders, G. F. Effect of different tryptophan sources on amino acids availability to the brain and mood in healthy volunteers. Psychopharmacology 201, 107\u2013114 (2008).","journal-title":"Psychopharmacology"},{"key":"81654_CR47","doi-asserted-by":"crossref","unstructured":"Fernstrom, J. D. & Fernstrom, M. H. Tyrosine, phenylalanine, and catecholamine synthesis and function in the brain. J. Nutr. 137, 1539S\u20131547S (2007) (discussion 1548S).","DOI":"10.1093\/jn\/137.6.1539S"},{"key":"81654_CR48","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1002\/j.1532-2149.2011.00066.x","volume":"16","author":"M Benedetti","year":"2012","unstructured":"Benedetti, M. et al. Plasma corticosterone levels in mouse models of pain. Eur. J. Pain Lond. Engl. 16, 803\u2013815 (2012).","journal-title":"Eur. J. Pain Lond. Engl."},{"key":"81654_CR49","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/S1043-2760(02)00004-8","volume":"14","author":"G Blackburn-Munro","year":"2003","unstructured":"Blackburn-Munro, G. & Blackburn-Munro, R. Pain in the brain: Are hormones to blame?. Trends Endocrinol. Metab. 14, 20\u201327 (2003).","journal-title":"Trends Endocrinol. Metab."},{"key":"81654_CR50","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1007\/s11916-004-0025-9","volume":"8","author":"G Blackburn-Munro","year":"2004","unstructured":"Blackburn-Munro, G. Hypothalamo\u2013pituitary\u2013adrenal axis dysfunction as a contributory factor to chronic pain and depression. Curr. Pain Headache Rep. 8, 116\u2013124 (2004).","journal-title":"Curr. Pain Headache Rep."},{"key":"81654_CR51","doi-asserted-by":"publisher","first-page":"8595","DOI":"10.1523\/JNEUROSCI.3058-04.2004","volume":"24","author":"S Wang","year":"2004","unstructured":"Wang, S. et al. Expression of central glucocorticoid receptors after peripheral nerve injury contributes to neuropathic pain behaviors in rats. J. Neurosci. Off. J. Soc. Neurosci. 24, 8595\u20138605 (2004).","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"81654_CR52","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1523\/JNEUROSCI.4127-04.2005","volume":"25","author":"S Wang","year":"2005","unstructured":"Wang, S. et al. Central glucocorticoid receptors modulate the expression and function of spinal NMDA receptors after peripheral nerve injury. J. Neurosci. Off. J. Soc. Neurosci. 25, 488\u2013495 (2005).","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"81654_CR53","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1126\/science.278.5339.876","volume":"278","author":"C Paszty","year":"1997","unstructured":"Paszty, C. et al. Transgenic knockout mice with exclusively human sickle hemoglobin and sickle cell disease. Science 278, 876\u2013878 (1997).","journal-title":"Science"},{"key":"81654_CR54","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1053\/eujp.2000.0189","volume":"4","author":"B Van Houdenhove","year":"2000","unstructured":"Van Houdenhove, B. Psychosocial stress and chronic pain. Eur. J. Pain 4, 225\u2013228 (2000).","journal-title":"Eur. J. Pain"},{"key":"81654_CR55","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/j.psyneuen.2007.11.004","volume":"33","author":"BM Elzinga","year":"2008","unstructured":"Elzinga, B. M. et al. Diminished cortisol responses to psychosocial stress associated with lifetime adverse events: A study among healthy young subjects. Psychoneuroendocrinology 33, 227\u2013237 (2008).","journal-title":"Psychoneuroendocrinology"},{"key":"81654_CR56","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1016\/j.biopsych.2005.12.006","volume":"60","author":"W Saltzman","year":"2006","unstructured":"Saltzman, W., Hogan, B. K. & Abbott, D. H. Diminished cortisol levels in subordinate female marmosets are associated with altered central drive to the hypothalamic\u2013pituitary\u2013adrenal axis. Biol. Psychiatry 60, 843\u2013849 (2006).","journal-title":"Biol. Psychiatry"},{"key":"81654_CR57","doi-asserted-by":"publisher","first-page":"809","DOI":"10.2147\/JPR.S164128","volume":"11","author":"Y Uchio","year":"2018","unstructured":"Uchio, Y. et al. A randomized, double-blind, placebo-controlled Phase III trial of duloxetine in Japanese patients with knee pain due to osteoarthritis. J. Pain Res. 11, 809\u2013821 (2018).","journal-title":"J. Pain Res."},{"key":"81654_CR58","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2017.10.004","author":"A Neville","year":"2017","unstructured":"Neville, A., Soltani, S., Pavlova, M. & Noel, M. Unravelling the Relationship between Parent and Child PTSD and Pediatric Chronic Pain: the Mediating Role of Pain Catastrophizing. J. Pain Off. J. Am. Pain Soc. https:\/\/doi.org\/10.1016\/j.jpain.2017.10.004 (2017).","journal-title":"J. Pain Off. J. Am. Pain Soc."},{"key":"81654_CR59","doi-asserted-by":"publisher","first-page":"e111765","DOI":"10.1371\/journal.pone.0111765","volume":"9","author":"JS Merlin","year":"2014","unstructured":"Merlin, J. S. et al. \u2018Two Pains Together\u2019: Patient perspectives on psychological aspects of chronic pain while living with HIV. PLoS ONE 9, e111765 (2014).","journal-title":"PLoS ONE"},{"key":"81654_CR60","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/S1529-9430(01)00054-7","volume":"1","author":"AR Block","year":"2001","unstructured":"Block, A. R., Ohnmeiss, D. D., Guyer, R. D., Rashbaum, R. F. & Hochschuler, S. H. The use of presurgical psychological screening to predict the outcome of spine surgery. Spine J. Off. J. N. Am. Spine Soc. 1, 274\u2013282 (2001).","journal-title":"Spine J. Off. J. N. Am. Spine Soc."},{"key":"81654_CR61","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1097\/00002508-200301000-00003","volume":"19","author":"TE Rudy","year":"2003","unstructured":"Rudy, T. E., Lieber, S. J., Boston, J. R., Gourley, L. M. & Baysal, E. Psychosocial predictors of physical performance in disabled individuals with chronic pain. Clin. J. Pain 19, 18\u201330 (2003).","journal-title":"Clin. J. Pain"},{"key":"81654_CR62","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1016\/j.ejpain.2008.07.015","volume":"13","author":"A Hinrichs-Rocker","year":"2009","unstructured":"Hinrichs-Rocker, A. et al. Psychosocial predictors and correlates for chronic post-surgical pain (CPSP)\u2014A systematic review. Eur. J. Pain 13, 719\u2013730 (2009).","journal-title":"Eur. J. Pain"},{"key":"81654_CR63","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1016\/j.jpain.2016.08.003","volume":"17","author":"VA Mathur","year":"2016","unstructured":"Mathur, V. A. et al. Disease-related, nondisease-related, and situational catastrophizing in sickle cell disease and its relationship with pain. J. Pain Off. J. Am. Pain Soc. 17, 1227\u20131236 (2016).","journal-title":"J. Pain Off. J. Am. Pain Soc."},{"key":"81654_CR64","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/S0304-3959(99)00183-9","volume":"84","author":"JL Rhudy","year":"2000","unstructured":"Rhudy, J. L. & Meagher, M. W. Fear and anxiety: Divergent effects on human pain thresholds. Pain 84, 65\u201375 (2000).","journal-title":"Pain"},{"key":"81654_CR65","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1111\/j.1469-8986.2005.00310.x","volume":"42","author":"R Kenntner-Mabiala","year":"2005","unstructured":"Kenntner-Mabiala, R. & Pauli, P. Affective modulation of brain potentials to painful and nonpainful stimuli. Psychophysiology 42, 559\u2013567 (2005).","journal-title":"Psychophysiology"},{"key":"81654_CR66","first-page":"987","volume":"47","author":"K Wiech","year":"2009","unstructured":"Wiech, K. & Tracey, I. The influence of negative emotions on pain: Behavioral effects and neural mechanisms. Brain Body Med. 47, 987\u2013994 (2009).","journal-title":"Brain Body Med."},{"key":"81654_CR67","doi-asserted-by":"publisher","first-page":"e0183354","DOI":"10.1371\/journal.pone.0183354","volume":"12","author":"PO Coffin","year":"2017","unstructured":"Coffin, P. O. et al. Behavioral intervention to reduce opioid overdose among high-risk persons with opioid use disorder: A pilot randomized controlled trial. PLoS ONE 12, e0183354 (2017).","journal-title":"PLoS ONE"},{"key":"81654_CR68","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1111\/j.1467-789X.2006.00270.x","volume":"8","author":"MD Klok","year":"2007","unstructured":"Klok, M. D., Jakobsdottir, S. & Drent, M. L. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: A review. Obes. Rev. 8, 21\u201334 (2007).","journal-title":"Obes. Rev."},{"key":"81654_CR69","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.peptides.2015.10.002","volume":"74","author":"DJ Haleem","year":"2015","unstructured":"Haleem, D. J., Haque, Z., Inam, Q.-A., Ikram, H. & Haleem, M. A. Behavioral, hormonal and central serotonin modulating effects of injected leptin. Peptides 74, 1\u20138 (2015).","journal-title":"Peptides"},{"key":"81654_CR70","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/j.biopsych.2012.03.010","volume":"72","author":"SJ Spencer","year":"2012","unstructured":"Spencer, S. J. et al. Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress. Biol. Psychiatry 72, 457\u2013465 (2012).","journal-title":"Biol. Psychiatry"},{"key":"81654_CR71","doi-asserted-by":"publisher","first-page":"2433","DOI":"10.1001\/archinte.163.20.2433","volume":"163","author":"MJ Bair","year":"2003","unstructured":"Bair, M. J., Robinson, R. L., Katon, W. & Kroenke, K. Depression and pain comorbidity: A literature review. Arch. Intern. Med. 163, 2433\u20132445 (2003).","journal-title":"Arch. Intern. Med."},{"key":"81654_CR72","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1097\/FBP.0b013e328349aae4","volume":"22","author":"L Bardin","year":"2011","unstructured":"Bardin, L. The complex role of serotonin and 5-HT receptors in chronic pain. Behav. Pharmacol. 22, 390\u2013404 (2011).","journal-title":"Behav. Pharmacol."},{"key":"81654_CR73","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1016\/j.neuropharm.2008.06.036","volume":"55","author":"CJ Harmer","year":"2008","unstructured":"Harmer, C. J. Serotonin and emotional processing: Does it help explain antidepressant drug action?. Neuropharmacology 55, 1023\u20131028 (2008).","journal-title":"Neuropharmacology"},{"key":"81654_CR74","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1385\/MN:30:2:117","volume":"30","author":"C Sommer","year":"2004","unstructured":"Sommer, C. Serotonin in pain and analgesia. Mol. Neurobiol. 30, 117\u2013125 (2004).","journal-title":"Mol. Neurobiol."},{"key":"81654_CR75","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1586\/14737175.8.5.781","volume":"8","author":"PB Wood","year":"2008","unstructured":"Wood, P. B. Role of central dopamine in pain and analgesia. Expert Rev. Neurother. 8, 781\u2013797 (2008).","journal-title":"Expert Rev. Neurother."},{"key":"81654_CR76","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.pain.2009.09.020","volume":"147","author":"Z Song","year":"2009","unstructured":"Song, Z., Ultenius, C., Meyerson, B. A. & Linderoth, B. Pain relief by spinal cord stimulation involves serotonergic mechanisms: An experimental study in a rat model of mononeuropathy. Pain 147, 241\u2013248 (2009).","journal-title":"Pain"},{"key":"81654_CR77","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/1043-6618(92)91387-V","volume":"25","author":"MO Carruba","year":"1992","unstructured":"Carruba, M. O. et al. Catecholamine and serotonin depletion from rat spinal cord: Effects on morphine and footshock induced analgesia. Pharmacol. Res. 25, 187\u2013194 (1992).","journal-title":"Pharmacol. Res."},{"key":"81654_CR78","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/S0304-3959(99)00307-3","volume":"86","author":"L Bardin","year":"2000","unstructured":"Bardin, L., Lavarenne, J. & Eschalier, A. Serotonin receptor subtypes involved in the spinal antinociceptive effect of 5-HT in rats. Pain 86, 11\u201318 (2000).","journal-title":"Pain"},{"issue":"15","key":"81654_CR79","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1089\/jwh.2006.15.146","volume":"2002","author":"DK McClish","year":"2006","unstructured":"McClish, D. K. et al. Gender differences in pain and healthcare utilization for adult sickle cell patients: The PiSCES Project. J. Womens Health 2002(15), 146\u2013154 (2006).","journal-title":"J. Womens Health"},{"key":"81654_CR80","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1016\/j.jpain.2008.12.001","volume":"10","author":"RB Fillingim","year":"2009","unstructured":"Fillingim, R. B., King, C. D., Ribeiro-Dasilva, M. C., Rahim-Williams, B. & Riley, J. L. Sex, gender, and pain: A review of recent clinical and experimental findings. J. Pain Off. J. Am. Pain Soc. 10, 447\u2013485 (2009).","journal-title":"J. Pain Off. J. Am. Pain Soc."},{"key":"81654_CR81","first-page":"141","volume":"186","author":"JS Mogil","year":"2010","unstructured":"Mogil, J. S. & Bailey, A. L. Sex and gender differences in pain and analgesia. Prog. Brain Res. 186, 141\u2013157 (2010).","journal-title":"Prog. Brain Res."},{"key":"81654_CR82","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1038\/nrn3360","volume":"13","author":"JS Mogil","year":"2012","unstructured":"Mogil, J. S. Sex differences in pain and pain inhibition: Multiple explanations of a controversial phenomenon. Nat. Rev. Neurosci. 13, 859\u2013866 (2012).","journal-title":"Nat. Rev. Neurosci."},{"key":"81654_CR83","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1097\/MPH.0000000000000265","volume":"37","author":"AM Brandow","year":"2015","unstructured":"Brandow, A. M., Farley, R. A., Dasgupta, M., Hoffmann, R. G. & Panepinto, J. A. The use of neuropathic pain drugs in children with sickle cell disease is associated with older age, female sex, and longer length of hospital stay. J. Pediatr. Hematol. Oncol. 37, 10\u201315 (2015).","journal-title":"J. Pediatr. Hematol. Oncol."},{"key":"81654_CR84","first-page":"211","volume":"17","author":"D Ortolani","year":"2014","unstructured":"Ortolani, D., Garcia, M. C., Melo-Thomas, L. & Spadari-Bratfisch, R. C. Stress-induced endocrine response and anxiety: The effects of comfort food in rats. Stress Amst. Neth. 17, 211\u2013218 (2014).","journal-title":"Stress Amst. Neth."},{"key":"81654_CR85","first-page":"514","volume":"18","author":"C de Oliveira","year":"2015","unstructured":"de Oliveira, C. et al. Hypercaloric diet modulates effects of chronic stress: A behavioral and biometric study on rats. Stress Amst. Neth. 18, 514\u2013523 (2015).","journal-title":"Stress Amst. Neth."},{"key":"81654_CR86","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/S0306-4530(98)00050-X","volume":"24","author":"MA Ruis","year":"1999","unstructured":"Ruis, M. A. et al. Housing familiar male wildtype rats together reduces the long-term adverse behavioural and physiological effects of social defeat. Psychoneuroendocrinology 24, 285\u2013300 (1999).","journal-title":"Psychoneuroendocrinology"},{"key":"81654_CR87","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/j.physbeh.2004.01.011","volume":"81","author":"S Dronjak","year":"2004","unstructured":"Dronjak, S., Gavrilovi\u0107, L., Filipovi\u0107, D. & Radojci\u0107, M. B. Immobilization and cold stress affect sympatho-adrenomedullary system and pituitary-adrenocortical axis of rats exposed to long-term isolation and crowding. Physiol. Behav. 81, 409\u2013415 (2004).","journal-title":"Physiol. Behav."},{"key":"81654_CR88","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/0304-3959(86)90224-1","volume":"27","author":"RA Sternbach","year":"1986","unstructured":"Sternbach, R. A. Pain and \u2018hassles\u2019 in the united states: Findings of the nuprin pain report. Pain 27, 69\u201380 (1986).","journal-title":"Pain"},{"key":"81654_CR89","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1007\/s12160-013-9583-6","volume":"48","author":"MC Davis","year":"2014","unstructured":"Davis, M. C., Thummala, K. & Zautra, A. J. Stress-related clinical pain and mood in women with chronic pain: Moderating effects of depression and positive mood induction. Ann. Behav. Med. Publ. Soc. Behav. Med. 48, 61\u201370 (2014).","journal-title":"Ann. Behav. Med. Publ. Soc. Behav. Med."},{"key":"81654_CR90","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/bs.irn.2015.10.003","volume":"125","author":"L Corcoran","year":"2015","unstructured":"Corcoran, L., Roche, M. & Finn, D. P. The role of the brain\u2019s endocannabinoid system in pain and its modulation by stress. Int. Rev. Neurobiol. 125, 203\u2013255 (2015).","journal-title":"Int. Rev. Neurobiol."},{"key":"81654_CR91","doi-asserted-by":"publisher","first-page":"1816","DOI":"10.2522\/ptj.20130597","volume":"94","author":"KE Hannibal","year":"2014","unstructured":"Hannibal, K. E. & Bishop, M. D. Chronic stress, cortisol dysfunction, and pain: A psychoneuroendocrine rationale for stress management in pain rehabilitation. Phys. Ther. 94, 1816\u20131825 (2014).","journal-title":"Phys. Ther."},{"key":"81654_CR92","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1080\/07347332.2017.1331492","volume":"35","author":"JB Reese","year":"2017","unstructured":"Reese, J. B., Lepore, S. J., Handorf, E. A. & Haythornthwaite, J. A. Emotional approach coping and depressive symptoms in colorectal cancer patients: The role of the intimate relationship. J. Psychosoc. Oncol. 35, 578\u2013596 (2017).","journal-title":"J. Psychosoc. Oncol."},{"key":"81654_CR93","doi-asserted-by":"publisher","first-page":"4496","DOI":"10.1210\/en.2011-1218","volume":"152","author":"R Yehuda","year":"2011","unstructured":"Yehuda, R. & Seckl, J. Minireview: Stress-related psychiatric disorders with low cortisol levels: A metabolic hypothesis. Endocrinology 152, 4496\u20134503 (2011).","journal-title":"Endocrinology"},{"key":"81654_CR94","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1177\/1535370214531863","volume":"239","author":"EA Manci","year":"2014","unstructured":"Manci, E. A. et al. High protein diet attenuates histopathologic organ damage and vascular leakage in transgenic murine model of sickle cell anemia. Exp. Biol. Med. 239, 966\u2013974 (2014).","journal-title":"Exp. Biol. Med."},{"key":"81654_CR95","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/nri.2015.5","volume":"16","author":"AH Miller","year":"2016","unstructured":"Miller, A. H. & Raison, C. L. The role of inflammation in depression: From evolutionary imperative to modern treatment target. Nat. Rev. Immunol. 16, 22\u201334 (2016).","journal-title":"Nat. Rev. Immunol."},{"key":"81654_CR96","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1038\/npp.2016.90","volume":"42","author":"C M\u00e9nard","year":"2017","unstructured":"M\u00e9nard, C., Pfau, M. L., Hodes, G. E. & Russo, S. J. Immune and neuroendocrine mechanisms of stress vulnerability and resilience. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 42, 62\u201380 (2017).","journal-title":"Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol."},{"key":"81654_CR97","doi-asserted-by":"publisher","first-page":"1386","DOI":"10.1038\/nn.4113","volume":"18","author":"GE Hodes","year":"2015","unstructured":"Hodes, G. E., Kana, V., Menard, C., Merad, M. & Russo, S. J. Neuroimmune mechanisms of depression. Nat. Neurosci. 18, 1386\u20131393 (2015).","journal-title":"Nat. Neurosci."},{"key":"81654_CR98","doi-asserted-by":"publisher","first-page":"16136","DOI":"10.1073\/pnas.1415191111","volume":"111","author":"GE Hodes","year":"2014","unstructured":"Hodes, G. E. et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc. Natl. Acad. Sci. U. S. A. 111, 16136\u201316141 (2014).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"81654_CR99","doi-asserted-by":"publisher","first-page":"16574","DOI":"10.1073\/pnas.1310655110","volume":"110","author":"ND Powell","year":"2013","unstructured":"Powell, N. D. et al. Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via \u03b2-adrenergic induction of myelopoiesis. Proc. Natl. Acad. Sci. USA 110, 16574\u201316579 (2013).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"81654_CR100","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1038\/s41593-017-0010-3","volume":"20","author":"C Menard","year":"2017","unstructured":"Menard, C. et al. Social stress induces neurovascular pathology promoting depression. Nat. Neurosci. 20, 1752 (2017).","journal-title":"Nat. Neurosci."},{"key":"81654_CR101","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/S0006-8993(00)03026-2","volume":"888","author":"P Esposito","year":"2001","unstructured":"Esposito, P. et al. Acute stress increases permeability of the blood\u2013brain-barrier through activation of brain mast cells. Brain Res. 888, 117\u2013127 (2001).","journal-title":"Brain Res."},{"key":"81654_CR102","first-page":"111","volume":"25","author":"HS Sharma","year":"1981","unstructured":"Sharma, H. S. & Dey, P. K. Impairment of blood\u2013brain barrier (BBB) in rat by immobilization stress: Role of serotonin (5-HT). Indian J. Physiol. Pharmacol. 25, 111\u2013122 (1981).","journal-title":"Indian J. Physiol. Pharmacol."},{"key":"81654_CR103","doi-asserted-by":"publisher","first-page":"13820","DOI":"10.1523\/JNEUROSCI.1671-13.2013","volume":"33","author":"ES Wohleb","year":"2013","unstructured":"Wohleb, E. S., Powell, N. D., Godbout, J. P. & Sheridan, J. F. Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. J. Neurosci. Off. J. Soc. Neurosci. 33, 13820\u201313833 (2013).","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"81654_CR104","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1016\/j.jpain.2016.01.475","volume":"17","author":"CM Campbell","year":"2016","unstructured":"Campbell, C. M. et al. An evaluation of central sensitization in patients with sickle cell disease. J. Pain Off. J. Am. Pain Soc. 17, 617\u2013627 (2016).","journal-title":"J. Pain Off. J. Am. Pain Soc."},{"key":"81654_CR105","doi-asserted-by":"publisher","first-page":"S69","DOI":"10.1016\/j.amepre.2016.02.012","volume":"51","author":"CP Carroll","year":"2016","unstructured":"Carroll, C. P. et al. chronic opioid therapy and central sensitization in sickle cell disease. Am. J. Prev. Med. 51, S69-77 (2016).","journal-title":"Am. J. Prev. Med."},{"key":"81654_CR106","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1172\/JCI15956","volume":"111","author":"CED Lamming","year":"2003","unstructured":"Lamming, C. E. D. et al. Spontaneous circulation of myeloid-lymphoid\u2013initiating cells and SCID-repopulating cells in sickle cell crisis. J. Clin. Invest. 111, 811\u2013819 (2003).","journal-title":"J. Clin. Invest."},{"key":"81654_CR107","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1089\/jir.1995.15.1061","volume":"15","author":"SC Taylor","year":"1995","unstructured":"Taylor, S. C., Shacks, S. J., Mitchell, R. A. & Banks, A. Serum interleukin-6 levels in the steady state of sickle cell disease. J. Interferon Cytokine Res Off. J. Int. Soc. Interferon Cytokine Res. 15, 1061\u20131064 (1995).","journal-title":"J. Interferon Cytokine Res Off. J. Int. Soc. Interferon Cytokine Res."},{"key":"81654_CR108","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1016\/j.autrev.2006.02.010","volume":"5","author":"Y Barak","year":"2006","unstructured":"Barak, Y. The immune system and happiness. Autoimmun. Rev. 5, 523\u2013527 (2006).","journal-title":"Autoimmun. Rev."},{"key":"81654_CR109","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/j.jpsychores.2011.05.009","volume":"71","author":"ERH Wilson","year":"2011","unstructured":"Wilson, E. R. H. et al. Do illness perceptions and mood predict healing time for burn wounds? A prospective, preliminary study. J. Psychosom. Res. 71, 364\u2013366 (2011).","journal-title":"J. Psychosom. Res."},{"key":"81654_CR110","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1188\/08.ONF.225-232","volume":"35","author":"RA Johnson","year":"2008","unstructured":"Johnson, R. A., Meadows, R. L., Haubner, J. S. & Sevedge, K. Animal-assisted activity among patients with cancer: effects on mood, fatigue, self-perceived health, and sense of coherence. Oncol. Nurs. Forum 35, 225\u2013232 (2008).","journal-title":"Oncol. Nurs. Forum"},{"key":"81654_CR111","doi-asserted-by":"publisher","first-page":"S71","DOI":"10.1089\/acm.2004.10.S-71","volume":"10","author":"M Schweitzer","year":"2004","unstructured":"Schweitzer, M., Gilpin, L. & Frampton, S. Healing spaces: Elements of environmental design that make an impact on health. J. Altern. Complement. Med. 10, S71 (2004).","journal-title":"J. Altern. Complement. Med."},{"key":"81654_CR112","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.ctcp.2009.05.004","volume":"15","author":"AB Coakley","year":"2009","unstructured":"Coakley, A. B. & Mahoney, E. K. Creating a therapeutic and healing environment with a pet therapy program. Complement. Ther. Clin. Pract. 15, 141\u2013146 (2009).","journal-title":"Complement. Ther. Clin. Pract."},{"key":"81654_CR113","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.3324\/haematol.2013.086637","volume":"98","author":"CR Morris","year":"2013","unstructured":"Morris, C. R. et al. A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes. Haematologica 98, 1375\u20131382 (2013).","journal-title":"Haematologica"},{"key":"81654_CR114","doi-asserted-by":"publisher","first-page":"1598","DOI":"10.1182\/bloodadvances.2017007211","volume":"1","author":"JWR Sins","year":"2017","unstructured":"Sins, J. W. R., Mager, D. J., Davis, S. C. A. T., Biemond, B. J. & Fijnvandraat, K. Pharmacotherapeutical strategies in the prevention of acute, vaso-occlusive pain in sickle cell disease: A systematic review. Blood Adv. 1, 1598\u20131616 (2017).","journal-title":"Blood Adv."},{"key":"81654_CR115","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.ebiom.2018.06.023","volume":"33","author":"HI Hyacinth","year":"2018","unstructured":"Hyacinth, H. I. The injured brain might need more fat!. EBioMedicine 33, 12\u201313 (2018).","journal-title":"EBioMedicine"},{"key":"81654_CR116","doi-asserted-by":"publisher","first-page":"e130","DOI":"10.1016\/S2352-3026(18)30032-2","volume":"5","author":"HI Hyacinth","year":"2018","unstructured":"Hyacinth, H. I. Sickle-cell anaemia needs more food?. Lancet Haematol. 5, e130\u2013e131 (2018).","journal-title":"Lancet Haematol."},{"key":"81654_CR117","doi-asserted-by":"publisher","first-page":"e331","DOI":"10.3324\/haematol.2018.208322","volume":"104","author":"OB Jahagirdar","year":"2019","unstructured":"Jahagirdar, O. B. et al. Diet and gender influence survival of transgenic Berkley sickle cell mice. Haematologica 104, e331 (2019).","journal-title":"Haematologica"},{"key":"81654_CR118","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1182\/blood-2010-01-260372","volume":"116","author":"DR Kohli","year":"2010","unstructured":"Kohli, D. R. et al. Pain-related behaviors and neurochemical alterations in mice expressing sickle hemoglobin: Modulation by cannabinoids. Blood 116, 456\u2013465 (2010).","journal-title":"Blood"},{"key":"81654_CR119","doi-asserted-by":"publisher","first-page":"57","DOI":"10.4137\/NMI.S5048","volume":"3","author":"HI Hyacinth","year":"2010","unstructured":"Hyacinth, H. I., Gee, B. E. & Hibbert, J. M. The role of nutrition in sickle cell disease. Nutr. Metab. Insights 3, 57\u201367 (2010).","journal-title":"Nutr. Metab. Insights"},{"key":"81654_CR120","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1124\/jpet.104.070656","volume":"311","author":"S Iyengar","year":"2004","unstructured":"Iyengar, S., Webster, A. A., Hemrick-Luecke, S. K., Xu, J. Y. & Simmons, R. M. A. Efficacy of duloxetine, a potent and balanced serotonin-norepinephrine reuptake inhibitor in persistent pain models in rats. J. Pharmacol. Exp. Ther. 311, 576\u2013584 (2004).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"81654_CR121","volume-title":"The Allen Reference Atlas: A Digital Color Brain Atlas of the C57Bl\/6J Male Mouse","author":"HW Dong","year":"2008","unstructured":"Dong, H. W. The Allen Reference Atlas: A Digital Color Brain Atlas of the C57Bl\/6J Male Mouse (Wiley, New York, 2008)."},{"key":"81654_CR122","doi-asserted-by":"publisher","first-page":"1853","DOI":"10.1182\/blood-2013-04-498105","volume":"122","author":"L Vincent","year":"2013","unstructured":"Vincent, L. et al. Mast cell activation contributes to sickle cell pathobiology and pain in mice. Blood 122, 1853\u20131862 (2013).","journal-title":"Blood"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-81654-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-81654-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-81654-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,28]],"date-time":"2023-01-28T10:34:24Z","timestamp":1674902064000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-81654-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,1]]},"references-count":122,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["81654"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-81654-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,1]]},"assertion":[{"value":"30 May 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 January 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 February 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Kalpna Gupta: Honoraria: <i>Tautona Group<\/i>, <i>Novartis<\/i> and <i>CSL Behring<\/i>. Research Grants: <i>Cyclerion<\/i>, <i>1910 Genetics<\/i> and <i>Grifols<\/i>. None of these have a conflict with the present work. All other authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2330"}}