{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T01:31:49Z","timestamp":1781227909167,"version":"3.54.1"},"reference-count":88,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T00:00:00Z","timestamp":1695168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kuwait University Research Sector","award":["YM05\/19"],"award-info":[{"award-number":["YM05\/19"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neuropathic pain is a well-documented phenomenon in experimental and clinical diabetes; however, current treatment is unsatisfactory. Serotoninergic-containing neurons are key components of the descending autoinhibitory pathway, and a decrease in their activity may contribute at least in part to diabetic neuropathic pain (DNP). A streptozotocin (STZ)-treated rat was used as a model for type 1 diabetes mellitus (T1DM). Pain transmission was evaluated using well-established nociceptive-based techniques, including the Hargreaves apparatus, cold plate and dynamic plantar aesthesiometer. Using qRT-PCR, Western blotting, immunohistochemistry, and HPLC-based techniques, we also measured in the central nervous system and peripheral nervous system of diabetic animals the expression and localization of 5-HT1A receptors (5-HT1AR), levels of key enzymes involved in the synthesis and degradation of tryptophan and 5-HT, including tryptophan hydroxylase-2 (Tph-2), tryptophan 2,3-dioxygenase (Tdo), indoleamine 2,3-dioxygenase 1 (Ido1) and Ido2. Moreover, spinal concentrations of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA, a metabolite of 5-HT) and quinolinic acid (QA, a metabolite of tryptophan) were also quantified. Diabetic rats developed thermal hyperalgesia and cold\/mechanical allodynia, and these behavioral abnormalities appear to be associated with the upregulation in the levels of expression of critical molecules related to the serotoninergic nervous system, including presynaptic 5-HT1AR and the enzymes Tph-2, Tdo, Ido1 and Ido2. Interestingly, the level of postsynaptic 5-HT1AR remains unaltered in STZ-induced T1DM. Chronic treatment of diabetic animals with 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT), a selective 5-HT1AR agonist, downregulated the upregulation of neuronal presynaptic 5-HT1AR, increased spinal release of 5-HT (\u2191 5-HIAA\/5-HT) and reduced the concentration of QA, decreased mRNA expression of Tdo, Ido1 and Ido2, arrested neuronal degeneration and ameliorated pain-related behavior as exemplified by thermal hyperalgesia and cold\/mechanical allodynia. These data show that 8-OH-DPAT alleviates DNP and other components of the serotoninergic system, including the ratio of 5-HIAA\/5-HT and 5-HT1AR, and could be a useful therapeutic agent for managing DNP.<\/jats:p>","DOI":"10.3390\/ijms241814334","type":"journal-article","created":{"date-parts":[[2023,9,20]],"date-time":"2023-09-20T21:26:32Z","timestamp":1695245192000},"page":"14334","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Activation of 5-HT1A Receptors Normalizes the Overexpression of Presynaptic 5-HT1A Receptors and Alleviates Diabetic Neuropathic Pain"],"prefix":"10.3390","volume":"24","author":[{"given":"Neha","family":"Munawar","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Medicine, Kuwait University, Al-Jabriya 046302, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milad S.","family":"Bitar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Medicine, Kuwait University, Al-Jabriya 046302, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3132-5935","authenticated-orcid":false,"given":"Willias","family":"Masocha","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, College of Pharmacy, Kuwait University, Al-Jabriya 046302, Kuwait"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1007\/s11892-019-1212-8","article-title":"Epidemiology of Peripheral Neuropathy and Lower Extremity Disease in Diabetes","volume":"19","author":"Hicks","year":"2019","journal-title":"Curr. Diabetes Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.pain.2013.11.013","article-title":"Neuropathic pain in the general population: A systematic review of epidemiological studies","volume":"155","author":"Austin","year":"2014","journal-title":"Pain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1900\/RDS.2015.12.63","article-title":"Treating Diabetic Neuropathy: Present Strategies and Emerging Solutions","volume":"12","author":"Javed","year":"2015","journal-title":"Rev. Diabet. Stud."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/0304-3959(78)90035-0","article-title":"Depression of primate spinothalamic tract neurons by iontophoretic application of 5-hydroxytryptamine","volume":"5","author":"Jordan","year":"1978","journal-title":"Pain"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1097\/FBP.0b013e328349aae4","article-title":"The complex role of serotonin and 5-HT receptors in chronic pain","volume":"22","author":"Bardin","year":"2011","journal-title":"Behav. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2929","DOI":"10.1007\/s00213-017-4686-6","article-title":"5-HT modulation of pain perception in humans","volume":"234","author":"Martin","year":"2017","journal-title":"Psychopharmacology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/S0301-0082(02)00009-6","article-title":"Descending control of pain","volume":"66","author":"Millan","year":"2002","journal-title":"Prog. Neurobiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.brainres.2009.05.001","article-title":"Differential mediation of descending pain facilitation and inhibition by spinal 5HT-3 and 5HT-7 receptors","volume":"1280","author":"Dogrul","year":"2009","journal-title":"Brain Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0304-3959(00)00346-8","article-title":"An excitatory role for 5-HT in spinal inflammatory nociceptive transmission; state-dependent actions via dorsal horn 5-HT(3) receptors in the anaesthetized rat","volume":"89","author":"Green","year":"2000","journal-title":"Pain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.neulet.2003.12.069","article-title":"Descending serotonergic facilitation mediated through rat spinal 5HT3 receptors is unaltered following carrageenan inflammation","volume":"361","author":"Rahman","year":"2004","journal-title":"Neurosci. Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.2174\/1570159X17666190811161807","article-title":"Targeting Serotonin1A Receptors for Treating Chronic Pain and Depression","volume":"17","author":"Haleem","year":"2019","journal-title":"Curr. Neuropharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1152\/physrev.1992.72.1.165","article-title":"Structure and function of the brain serotonin system","volume":"72","author":"Jacobs","year":"1992","journal-title":"Physiol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1002\/cne.1147","article-title":"Targeting of serotonin 1A receptors to dopaminergic neurons within the parabrachial subdivision of the ventral tegmental area in rat brain","volume":"433","author":"Doherty","year":"2001","journal-title":"J. Comp. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1523\/JNEUROSCI.12-02-00440.1992","article-title":"Distribution and cellular localization of mRNA coding for 5-HT1A receptor in the rat brain: Correlation with receptor binding","volume":"12","author":"Pompeiano","year":"1992","journal-title":"J. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e218","DOI":"10.1038\/cddis.2011.98","article-title":"Anatomical study of serotonergic innervation and 5-HT(1A) receptor in the human spinal cord","volume":"2","author":"Perrin","year":"2011","journal-title":"Cell Death Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1089\/neu.2008.0640","article-title":"Distribution and localization of 5-HT(1A) receptors in the rat lumbar spinal cord after transection and deafferentation","volume":"26","author":"Otoshi","year":"2009","journal-title":"J. Neurotrauma"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.1002\/cne.21665","article-title":"Genetically expressed transneuronal tracer reveals direct and indirect serotonergic descending control circuits","volume":"507","author":"Braz","year":"2008","journal-title":"J. Comp. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ejphar.2010.09.039","article-title":"Systemic cannabinoids produce CB(1)-mediated antinociception by activation of descending serotonergic pathways that act upon spinal 5-HT(7) and 5-HT(2A) receptors","volume":"649","author":"Seyrek","year":"2010","journal-title":"Eur. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/BF00964611","article-title":"L-kynurenine: Its synthesis and possible regulatory function in brain","volume":"5","author":"Gal","year":"1980","journal-title":"Neurochem. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5570","DOI":"10.1210\/en.2010-0745","article-title":"Minireview: New roles for peripheral dopamine on metabolic control and tumor growth: Let\u2019s seek the balance","volume":"151","author":"Rubi","year":"2010","journal-title":"Endocrinology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1111\/j.1460-9568.2005.04264.x","article-title":"Tissue-specific expression of tryptophan hydroxylase mRNAs in the rat midbrain: Anatomical evidence and daily profiles","volume":"22","author":"Malek","year":"2005","journal-title":"Eur. J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1210\/er.2018-00283","article-title":"Emerging Roles for Serotonin in Regulating Metabolism: New Implications for an Ancient Molecule","volume":"40","author":"Yabut","year":"2019","journal-title":"Endocr. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1196\/annals.1403.003","article-title":"Genetic and hormonal regulation of tryptophan kynurenine metabolism: Implications for vascular cognitive impairment, major depressive disorder, and aging","volume":"1122","author":"Oxenkrug","year":"2007","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/j.1471-4159.2007.04556.x","article-title":"Mitochondrial aspartate aminotransferase: A third kynurenate-producing enzyme in the mammalian brain","volume":"102","author":"Guidetti","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1002\/glia.20432","article-title":"Astrocytic localization of kynurenine aminotransferase II in the rat brain visualized by immunocytochemistry","volume":"55","author":"Guidetti","year":"2007","journal-title":"Glia"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/S0014-2999(01)01029-9","article-title":"In the formalin model of tonic nociceptive pain, 8-OH-DPAT produces 5-HT1A receptor-mediated, behaviorally specific analgesia","volume":"421","author":"Bardin","year":"2001","journal-title":"Eur. J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Munawar, N., Nader, J., Khadadah, N.H., Al Madhoun, A., Al-Ali, W., Varghese, L.A., Masocha, W., Al-Mulla, F., and Bitar, M.S. (2022). Guanfacine Normalizes the Overexpression of Presynaptic alpha-2A Adrenoceptor Signaling and Ameliorates Neuropathic Pain in a Chronic Animal Model of Type 1 Diabetes. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14102146"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"15","DOI":"10.33549\/physiolres.931903","article-title":"Serotonin receptors\u2014From molecular biology to clinical applications","volume":"60","author":"Pytliak","year":"2011","journal-title":"Physiol. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0091-3057(01)00576-7","article-title":"Effect of the serotonin agonist 8-OH-DPAT on the sensorimotor system of the rat","volume":"70","author":"Demeulemeester","year":"2001","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.neulet.2016.03.019","article-title":"Duloxetine and 8-OH-DPAT, but not fluoxetine, reduce depression-like behaviour in an animal model of chronic neuropathic pain","volume":"619","author":"Hu","year":"2016","journal-title":"Neurosci. Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.pneurobio.2012.06.010","article-title":"The serotonergic system in ageing and Alzheimer\u2019s disease","volume":"99","author":"Rodriguez","year":"2012","journal-title":"Prog. Neurobiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"963","DOI":"10.2147\/CIA.S133712","article-title":"The influence of the serotonergic system on the personality and quality of life of postmenopausal women","volume":"12","author":"Jurczak","year":"2017","journal-title":"Clin. Interv. Aging"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.bbr.2014.07.037","article-title":"Serotonin in Parkinson\u2019s disease","volume":"277","author":"Politis","year":"2015","journal-title":"Behav. Brain Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"781","DOI":"10.4155\/fmc-2017-0031","article-title":"Modulating 5-HT(4) and 5-HT(6) receptors in Alzheimer\u2019s disease treatment","volume":"9","author":"Lalut","year":"2017","journal-title":"Future Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s13041-017-0306-y","article-title":"The role of 5-HT receptors in depression","volume":"10","author":"Yohn","year":"2017","journal-title":"Mol. Brain"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"36553","DOI":"10.1074\/jbc.M203752200","article-title":"Serotonin 5-HT1A receptors regulate AMPA receptor channels through inhibiting Ca2+\/calmodulin-dependent kinase II in prefrontal cortical pyramidal neurons","volume":"277","author":"Cai","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/BF01245229","article-title":"Monoamine neurons in aging and Alzheimer\u2019s disease","volume":"91","author":"Palmer","year":"1993","journal-title":"J. Neural Transm. Gen. Sect."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/0006-8993(91)90171-Q","article-title":"Autoradiographic analysis of serotonin 5-HT1A receptor binding in the human brain postmortem: Effects of age and alcohol","volume":"554","author":"Dillon","year":"1991","journal-title":"Brain Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1111\/j.1471-4159.1984.tb06098.x","article-title":"Effect of age on human brain serotonin (S-1) binding sites","volume":"43","author":"Marcusson","year":"1984","journal-title":"J. Neurochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/S0893-133X(00)00227-X","article-title":"Serotonin 5-HT1A receptor binding potential declines with age as measured by [11C]WAY-100635 and PET","volume":"24","author":"Tauscher","year":"2001","journal-title":"Neuropsychopharmacology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1111\/j.1749-6632.1990.tb16896.x","article-title":"Aging and regenerative capacity of the rat serotonergic system. A morphological, neurochemical and behavioral analysis after transplantation of fetal raphe cells","volume":"600","author":"Steinbusch","year":"1990","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/0006-8993(93)91191-T","article-title":"Age-related changes on monoamine turnover in hippocampus of rats","volume":"631","author":"Venero","year":"1993","journal-title":"Brain Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S0091-3057(03)00065-0","article-title":"Presynaptic regulation of neurotransmitter release in the cortex of aged rats with differential memory impairments","volume":"75","author":"Birthelmer","year":"2003","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/S0361-9230(03)00042-X","article-title":"Presynaptic modulation of acetylcholine, noradrenaline, and serotonin release in the hippocampus of aged rats with various levels of memory impairments","volume":"60","author":"Birthelmer","year":"2003","journal-title":"Brain Res. Bull."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"197","DOI":"10.31887\/DCNS.2002.4.2\/rgur","article-title":"Gender differences in aging: Cognition, emotions, and neuroimaging studies","volume":"4","author":"Gur","year":"2002","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.bbr.2008.10.043","article-title":"Differential effects of exogenous and endogenous estrogen on anxiety as measured by elevated T-maze in relation to the serotonergic system","volume":"198","author":"Pandaranandaka","year":"2009","journal-title":"Behav. Brain Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1038\/sj.bjp.0702412","article-title":"Increased dopaminergic and 5-hydroxytryptaminergic activities in male rat brain following long-term treatment with anabolic androgenic steroids","volume":"126","author":"Thiblin","year":"1999","journal-title":"Br. J. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1210\/jcem.86.2.7219","article-title":"Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging","volume":"86","author":"Harman","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1111\/j.1365-2265.2004.02174.x","article-title":"Normal, bound and nonbound testosterone levels in normally ageing men: Results from the Massachusetts Male Ageing Study","volume":"62","author":"Mohr","year":"2005","journal-title":"Clin. Endocrinol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1093\/gerona\/gls068","article-title":"The role of androgens and estrogens on healthy aging and longevity","volume":"67","author":"Horstman","year":"2012","journal-title":"J. Gerontol. Biol. Sci. Med. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/S0014-2999(96)00819-9","article-title":"The effect of 5-HT1A receptor stimulation on nociceptive dorsal horn neurones in rats","volume":"318","author":"Gjerstad","year":"1996","journal-title":"Eur. J. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/0304-3959(92)90260-I","article-title":"Intrathecal co-administration of substance P and NMDA augments nociceptive responses in the formalin test","volume":"51","author":"Lund","year":"1992","journal-title":"Pain"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/0091-3057(86)90402-8","article-title":"Effects of the putative 5-HT1A receptor agonist 8-OH-2-(di-n-propylamino)tetralin on nociceptive sensitivity in mice","volume":"25","author":"Fasmer","year":"1986","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.jpain.2016.10.001","article-title":"Inhibition of Reinforcing, Hyperalgesic, and Motor Effects of Morphine by Buspirone in Rats","volume":"18","author":"Haleem","year":"2017","journal-title":"J. Pain."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/S0028-3908(99)00010-6","article-title":"A review of central 5-HT receptors and their function","volume":"38","author":"Barnes","year":"1999","journal-title":"Neuropharmacology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"144","DOI":"10.3389\/fpsyt.2017.00144","article-title":"Therapeutic Potential of Selectively Targeting the alpha(2C)-Adrenoceptor in Cognition, Depression, and Schizophrenia-New Developments and Future Perspective","volume":"8","author":"Uys","year":"2017","journal-title":"Front. Psychiatry"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.biochi.2018.10.015","article-title":"The 5-HT1A receptor: Signaling to behavior","volume":"161","author":"Albert","year":"2019","journal-title":"Biochimie"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.2337\/diabetes.52.9.2363","article-title":"Sensory neurons with activated caspase-3 survive long-term experimental diabetes","volume":"52","author":"Cheng","year":"2003","journal-title":"Diabetes"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"819","DOI":"10.2337\/diabetes.51.3.819","article-title":"Morphometry of dorsal root ganglion in chronic experimental diabetic neuropathy","volume":"51","author":"Kishi","year":"2002","journal-title":"Diabetes"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1242\/dmm.028225","article-title":"Diabetic polyneuropathy, sensory neurons, nuclear structure and spliceosome alterations: A role for CWC22","volume":"10","author":"Kobayashi","year":"2017","journal-title":"Dis. Model. Mech."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/0031-9384(91)90424-M","article-title":"The functional significance of biochemical alterations in streptozotocin-induced diabetes","volume":"50","author":"Bellush","year":"1991","journal-title":"Physiol. Behav."},{"key":"ref_62","first-page":"432","article-title":"Diabetes-induced alteration in brain monoamine metabolism in rats","volume":"236","author":"Bitar","year":"1986","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/sj.npp.1300354","article-title":"Diabetes attenuates the antidepressant-like effect mediated by the activation of 5-HT1A receptor in the mouse tail suspension test","volume":"29","author":"Miyata","year":"2004","journal-title":"Neuropsychopharmacology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.bbi.2015.06.022","article-title":"Indoleamine 2,3-dioxygenase-dependent neurotoxic kynurenine metabolism mediates inflammation-induced deficit in recognition memory","volume":"50","author":"Heisler","year":"2015","journal-title":"Brain Behav. Immun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1111\/j.1471-4159.2008.05241.x","article-title":"Kynurenine pathway metabolism in human blood-brain-barrier cells: Implications for immune tolerance and neurotoxicity","volume":"105","author":"Webster","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/s41573-019-0016-5","article-title":"Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond","volume":"18","author":"Platten","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1038\/npp.2010.39","article-title":"Reduction of endogenous kynurenic acid formation enhances extracellular glutamate, hippocampal plasticity, and cognitive behavior","volume":"35","author":"Potter","year":"2010","journal-title":"Neuropsychopharmacology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1007\/s12640-020-00192-2","article-title":"Intrastriatal Quinolinic Acid Administration Impairs Redox Homeostasis and Induces Inflammatory Changes: Prevention by Kynurenic Acid","volume":"38","author":"Ferreira","year":"2020","journal-title":"Neurotox. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1093\/brain\/115.5.1249","article-title":"Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease","volume":"115","author":"Heyes","year":"1992","journal-title":"Brain"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s10540-005-2896-3","article-title":"Transmembrane signaling in the brain by serotonin, a key regulator of physiology and emotion","volume":"25","author":"Adayev","year":"2005","journal-title":"Biosci. Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1177\/026988110001400208","article-title":"Serotonin autoreceptor function and antidepressant drug action","volume":"14","author":"Hjorth","year":"2000","journal-title":"J. Psychopharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1016\/j.cellsig.2010.03.019","article-title":"5-HT1A receptor-regulated signal transduction pathways in brain","volume":"22","author":"Polter","year":"2010","journal-title":"Cell Signal"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"5420","DOI":"10.1523\/JNEUROSCI.0950-04.2004","article-title":"Acute treatment with the antidepressant fluoxetine internalizes 5-HT1A autoreceptors and reduces the in vivo binding of the PET radioligand [18F]MPPF in the nucleus raphe dorsalis of rat","volume":"24","author":"Riad","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0006-8993(99)01284-6","article-title":"Spinal cord noradrenergic dynamics in diabetic and hypercortisolaemic states","volume":"830","author":"Bitar","year":"1999","journal-title":"Brain Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/S0014-2999(96)00693-0","article-title":"8-OH-DPAT-induced mydriasis in mice: A pharmacological characterisation","volume":"317","author":"Prow","year":"1996","journal-title":"Eur. J. Pharmacol."},{"key":"ref_76","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_77","doi-asserted-by":"crossref","first-page":"240508","DOI":"10.1155\/2013\/240508","article-title":"The anticonvulsant enaminone E139 attenuates paclitaxel-induced neuropathic pain in rodents","volume":"2013","author":"Thangamani","year":"2013","journal-title":"Sci. World J."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"30239","DOI":"10.1074\/jbc.273.46.30239","article-title":"The intracellular localization of deoxycytidine kinase","volume":"273","author":"Hatzis","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.jneuroim.2009.06.022","article-title":"Systemic lipopolysaccharide (LPS)-induced microglial activation results in different temporal reduction of CD200 and CD200 receptor gene expression in the brain","volume":"214","author":"Masocha","year":"2009","journal-title":"J. Neuroimmunol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Abdel-Halim, S.M., Al Madhoun, A., Nizam, R., Melhem, M., Cherian, P., Al-Khairi, I., Haddad, D., Abu-Farha, M., Abubaker, J., and Bitar, M.S. (2020). Increased Plasma Levels of Adenylate Cyclase 8 and cAMP Are Associated with Obesity and Type 2 Diabetes: Results from a Cross-Sectional Study. Biology, 9.","DOI":"10.3390\/biology9090244"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Al-Roub, A., Al Madhoun, A., Akhter, N., Thomas, R., Miranda, L., Jacob, T., Al-Ozairi, E., Al-Mulla, F., Sindhu, S., and Ahmad, R. (2021). IL-1beta and TNFalpha Cooperativity in Regulating IL-6 Expression in Adipocytes Depends on CREB Binding and H3K14 Acetylation. Cells, 10.","DOI":"10.3390\/cells10113228"},{"key":"ref_82","first-page":"5212852","article-title":"Chemically Defined Conditions Mediate an Efficient Induction of Dental Pulp Pluripotent-Like Stem Cells into Hepatocyte-Like Cells","volume":"2021","author":"Montori","year":"2021","journal-title":"Stem Cells Int."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"11893","DOI":"10.1038\/s41598-021-91092-8","article-title":"Microarray analysis reveals ONC201 mediated differential mechanisms of CHOP gene regulation in metastatic and nonmetastatic colorectal cancer cells","volume":"11","author":"Haddad","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Akhter, N., Wilson, A., Thomas, R., Al-Rashed, F., Kochumon, S., Al-Roub, A., Arefanian, H., Al-Madhoun, A., Al-Mulla, F., and Ahmad, R. (2021). ROS\/TNF-alpha Crosstalk Triggers the Expression of IL-8 and MCP-1 in Human Monocytic THP-1 Cells via the NF-kappaB and ERK1\/2 Mediated Signaling. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910519"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"16364","DOI":"10.1038\/s41598-020-73347-y","article-title":"Elevated adipose tissue associated IL-2 expression in obesity correlates with metabolic inflammation and insulin resistance","volume":"10","author":"Kochumon","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1111\/jnc.13109","article-title":"The role of parkinson\u2019s disease-associated receptor GPR37 in the hippocampus: Functional interplay with the adenosinergic system","volume":"134","author":"Lopes","year":"2015","journal-title":"J. Neurochem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s12272-015-0661-0","article-title":"Measuring levels of biogenic amines and their metabolites in rat brain tissue using high-performance liquid chromatography with photodiode array detection","volume":"39","author":"Gu","year":"2016","journal-title":"Arch. Pharm. Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1038\/emboj.2011.153","article-title":"Skeletal myosin light chain kinase regulates skeletal myogenesis by phosphorylation of MEF2C","volume":"30","author":"Mehta","year":"2011","journal-title":"EMBO J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/18\/14334\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:53:43Z","timestamp":1760129623000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/18\/14334"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,20]]},"references-count":88,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["ijms241814334"],"URL":"https:\/\/doi.org\/10.3390\/ijms241814334","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,20]]}}}