title: Nicotine stimulates expression of proteins implicated in peripheral and central sensitization.
abstract: Pain patients who are nicotine dependent report a significantly increased incidence and severity of pain intensity. The goal of this study was to determine the effects of prolonged nicotine administration on inflammatory proteins implicated in the development of peripheral and central sensitization of the trigeminal system. Behavioral, immunohistochemical, and microarray studies were utilized to investigate the effects of nicotine administered daily for 14 days via an Alzet® osmotic pump in Sprague Dawley rats. Systemic nicotine administration caused a significant increase in nocifensive withdrawals to mechanical stimulation of trigeminal neurons. Nicotine stimulated expression of the pro-inflammatory signal transduction proteins phosphorylated-extracellular signal-regulated kinase (p-ERK), phosphorylated-c-Jun N-terminal kinase (p-JNK), and protein kinase A (PKA) in the spinal trigeminal nucleus. Nicotine also promoted elevations in the expression of glial fibrillary acidic protein (GFAP), a biomarker of activated astrocytes, and the microglia biomarker ionized calcium-binding adapter molecule 1 (Iba1). Similarly, levels of eleven cytokines were significantly elevated with the largest increase in expression of TNF-α. Levels of PKA, p-ERK, and p-JNK in trigeminal ganglion neurons were increased by nicotine. Our findings demonstrate that prolonged systemic administration of nicotine promotes sustained behavioral and cellular changes in the expression of key proteins in the spinal trigeminal nucleus and trigeminal ganglion implicated in the development and maintenance of peripheral and central sensitization.
authors: Center for Biomedical & Life Sciences, Missouri State University, Springfield, MO, USA.
authors: J L
authors: JL
authors: Hawkins
authors: Center for Biomedical & Life Sciences, Missouri State University, Springfield, MO, USA.
authors: J E
authors: JE
authors: Denson
authors: Center for Biomedical & Life Sciences, Missouri State University, Springfield, MO, USA.
authors: D R
authors: DR
authors: Miley
authors: Center for Biomedical & Life Sciences, Missouri State University, Springfield, MO, USA. Electronic address: pauldurham@missouristate.edu.
authors: P L
authors: PL
authors: Durham
mesh_terms: D000818:Animals; D059333:Central Nervous System Sensitization / Q000187:drug effects* / Q000502:physiology; D003367:Cotinine / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D005731:Ganglionic Stimulants / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D009538:Nicotine / Q000494:pharmacology*; D059225:Nociception / Q000187:drug effects / Q000502:physiology; D010812:Physical Stimulation; D040081:Protein Array Analysis; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000187:drug effects* / Q000378:metabolism; D014279:Trigeminal Nucleus, Spinal / Q000187:drug effects* / Q000378:metabolism
chemical_list: D016207:Cytokines; D005731:Ganglionic Stimulants; D009538:Nicotine; D003367:Cotinine
keywords: central sensitization; cytokines; nicotine; spinal trigeminal nucleus; trigeminal ganglion
references: Mol Nutr Food Res. 2013 Jun;57(6):996-1006
references: 23576361
references: J Pain. 2009 Sep;10(9):895-926
references: 19712899
references: Autoimmun Rev. 2009 Mar;8(5):379-83
references: 19105984
references: Am J Physiol. 1996 Jun;270(6 Pt 1):C1807-14
references: 8764165
references: Eur Rev Med Pharmacol Sci. 2011 Oct;15(10):1111-6
references: 22165670
references: J Comp Neurol. 2004 Jan 12;468(3):322-33
references: 14681928
references: Psychopharmacology (Berl). 2006 Oct;188(2):152-61
references: 16915382
references: Headache. 2012 Jan;52(1):80-9
references: 22150557
references: J Headache Pain. 2011 Apr;12(2):157-72
references: 21390550
references: Neurochem Res. 2008 Oct;33(10):1970-8
references: 18427980
references: Headache. 2011 Jan;51(1):85-91
references: 20553330
references: J Neuroinflammation. 2005 Jan 25;2(1):4
references: 15670336
references: J Neurosci. 2008 Apr 23;28(17):4533-40
references: 18434532
references: Genes Dev. 2011 Oct 1;25(19):2069-78
references: 21979919
references: Brain Res Rev. 2009 Apr;60(1):135-48
references: 19150373
references: Headache. 2007 Jul-Aug;47(7):1050-5
references: 17635596
references: Headache. 2006 Nov;46 Suppl 4:S182-91
references: 17078850
references: Mol Pain. 2010 Dec 10;6:91
references: 21143976
references: J Orofac Pain. 2012 Fall;26(4):337-44
references: 23110274
references: Headache. 2013 Sep;53(8):1278-99
references: 23808666
references: Neuron. 2007 Aug 2;55(3):365-76
references: 17678851
references: J Neurosci. 2008 May 14;28(20):5189-94
references: 18480275
references: Handb Exp Pharmacol. 2009;(194):417-49
references: 19655114
references: Neuroscience. 2014 Jun 6;269:79-92
references: 24685439
references: J Neurosci. 2010 Aug 25;30(34):11537-47
references: 20739576
references: J Physiol. 2011 Dec 15;589(Pt 24):5941-7
references: 22041184
references: Pain Physician. 2008 Sep-Oct;11(5):643-53
references: 18850028
references: J Pharmacol Exp Ther. 1997 Jan;280(1):428-38
references: 8996225
references: Handb Exp Pharmacol. 2009;(194):451-91
references: 19655115
references: J Neurosci. 1999 Mar 15;19(6):2181-6
references: 10066271
references: PLoS One. 2011;6(11):e28142
references: 22140525
references: J Pharmacol Exp Ther. 2006 May;317(2):660-6
references: 16407464
references: Exp Brain Res. 2009 Jun;196(1):67-78
references: 19290516
references: J Neurosci. 2003 Feb 1;23(3):1026-40
references: 12574433
references: J Neurosci Res. 2005 Feb 15;79(4):535-44
references: 15635597
references: Annu Rev Physiol. 2013;75:365-91
references: 23190076
references: J Neuroinflammation. 2010 Apr 16;7:27
references: 20398373
references: J Headache Pain. 2013 May 07;14:40
references: 23651174
references: J Pharmacol Exp Ther. 2005 Aug;314(2):636-42
references: 15845856
references: J Neurosci. 2004 Sep 22;24(38):8310-21
references: 15385614
references: J Toxicol Pathol. 2013 Mar;26(1):55-60
references: 23723569
references: Brain Res. 1998 Nov 2;809(2):238-45
references: 9853116
references: Curr Drug Targets Inflamm Allergy. 2004 Sep;3(3):299-303
references: 15379598
references: Brain Res Rev. 2009 Apr;60(1):57-64
references: 19166877
references: J Neurochem. 2004 Dec;91(6):1417-29
references: 15584918
references: J Neurophysiol. 2004 Nov;92(5):2859-66
references: 15486424
references: Anat Rec (Hoboken). 2009 Dec;292(12):1902-13
references: 19943344
references: Pharmacol Rev. 2005 Mar;57(1):79-115
references: 15734728
references: Nicotine Tob Res. 2009 Dec;11(12):1407-14
references: 19828432
references: Anesthesiology. 2010 Oct;113(4):977-92
references: 20864835
references: J Neurosci. 1997 Oct 1;17(19):7462-70
references: 9295392
references: Glia. 2004 Jan 1;45(1):89-95
references: 14648549
references: Neuroscientist. 2010 Oct;16(5):519-31
references: 20581331
references: Biochem Biophys Res Commun. 2005 Sep 16;335(1):132-8
references: 16055088