Is inflammatory pulpal pain a risk factor for amnesia?

Document Type : Research Articles


1 Kerman University of Medical Sciences

2 Shahid Bahonar University

3 Mazandaran University of Medical Sciences

4 Mashhad University of Medical Sciences


The aim of this study was to investigate the effect of inflammatory pulpal pain on spatial learning and memory in male Wistar rats. Fifty-six adult rats were divided into eight groups as follows (n=7 per group): control, sham-operated group that received normal saline, sham vehicle group that received vehicle of capsaicin, three capsaicin treated groups that received intradental injection of 10, 25 and 100 μg capsaicin, respectively, formalin treated group that received 10 μl formalin 2.5% and ibuprofen treated group that received ibuprofen 20 min before capsaicin (100 μg) injection. After preparing cavities via cutting 2 mm of the distal extremities of the mandibular incisors, the polyethylene crowns were placed on the teeth. Based on the study group, different algesics were administrated under the crowns. After recording the pain scores, spatial learning and memory was assessed using Morris water maze test. Capsaicin 25, 100 μg and formalin 2.5% applications induced significantly more painful stimulation compared with control groups (p< 0.001). Capsaicin 25, 100 μg and also formalin-treated groups significantly showed increased escape latency and traveled distance (p


Abbott, N.J., Rönnbäck, L. and Hansson, E. (2006) Astrocyte–endothelial interactions at the blood–brain barrier. Nature Reviews Neuroscience 7, 41-53.
Apkarian, A.V., Sosa, Y., Krauss, B.R., Thomas, P.S. and Fredrickson, B.E. (2004) Chronic pain patients are impaired on an emotional decision-making task. Pain 108, 129-136.
Apkarian, A.V., Sosa, Y., Sonty, S., Levy, R.M., Harden, R.N. and Parrish, T.B. (2004) Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. The Journal of Neuroscience 24, 10410-10415.
Barha, C.K., Brummelte, S., Lieblich, S.E. and Galea, L.A.M. (2010) Chronic restraint stress in adolescence differentially influences hypothalamic pituitary adrenal axis function and adult hippocampal neurogenesis in male and female rats. Hippocampus 21, 1216-1227.
Barrientos, R.M., Higgins, E.A., Sprunger, D.B., Watkins, L.R., Rudy, J.W. and Maier, S.F. (2002) Memory for context is impaired by a post context exposure injection of interleukin-1 beta into dorsal hippocampus. Behavioural Brain Research 134, 291-298.
Bellinger, F.P., Madamba, S. and Siggins, G.R. (1993) Interleukin 1β inhibits synaptic strength and long-term potentiation in the rat CA1 hippocampus. Brain Research 628, 227-234.
Bergenholtz, G. (1981) Inflammatory response of the dental pulp to bacterial irritation. Journal of Endodontics 7, 100-104.
Boyette-Davis, J., Thompson, C. and Fuchs, P. (2008) Alterations in attentional mechanisms in response to acute inflammatory pain and morphine administration. Neuroscience 151, 558-563.
Ceccarelli, A., Rocca, M.A., Pagani, E., Falini, A., Comi, G. and Filippi, M. (2009) Cognitive learning is associated with gray matter changes in healthy human individuals: a tensor-based morphometry study. Neuroimage 48, 585-589.
Chidiac, J.J., Rifai, K., Hawwa, N.N., Massaad, C.A., Jurjus, A.R., Jabbur, S.J., (2002) Nociceptive behaviour induced by dental application of irritants to rat incisors: a new model for tooth inflammatory pain. European Journal of Pain 6, 55-67.
Cunningham, A.J., Murray, C.A., O'Neill, L.A.J., Lynch, M.A. and O'Connor, J.J. (1996) Interleukin-1β (IL-1β) and tumour necrosis factor (TNF) inhibit long-term potentiation in the rat dentate gyrus in vitro. Neuroscience Letters 203, 17-20.
Duric, V. and McCarson, K.E. (2006) Persistent pain produces stress-like alterations in hippocampal neurogenesis and gene expression. The Journal of Pain 7, 544-555.
Duric, V. and McCarson, K.E. (2007) Neurokinin-1 (NK-1) receptor and brain-derived neurotrophic factor (BDNF) gene expression is differentially modulated in the rat spinal dorsal horn and hippocampus during inflammatory pain. Molecular Pain 3, 32-41.
Egerton, A., Allison, C., Brett, R.R. and Pratt, J.A. (2006) Cannabinoids and prefrontal cortical function: insights from preclinical studies. Neuroscience & Biobehavioral Reviews 30, 680-695.
El Kouhen, O., Lehto, S., Pan, J., Chang, R., Baker, S. and Zhong, C. (2006) Blockade of mGluR1 receptor results in analgesia and disruption of motor and cognitive performances: effects of A841720, a novel non competitive mGluR1 receptor antagonist. British Journal of Pharmacology 149, 761-774.
Flirski, M. and Sobow, T. (2005) Biochemical Markers and Risk Factors of Alzheimers Disease. Current Alzheimer Research 2, 47-64.
Fossat, P., Turpin, F.R., Sacchi, S., Dulong, J., Shi, T. and Rivet, J.M. (2012) Glial D-serine gates NMDA receptors at excitatory synapses in prefrontal cortex. Cerebral Cortex 22, 595-606.
Gravius, A., Pietraszek, M., Dekundy, A. and Danysz, W. (2010) Metabotropic glutamate receptors as therapeutic targets for cognitive disorders. Current Topics in Medicinal Chemistry 10, 187-206.
Hariri, A.R., Goldberg, T.E., Mattay, V.S., Kolachana, B.S., Callicott, J.H., Egan, M.F. (2003) Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. The Journal of Neuroscience 23, 6690-6694.
Heapy, C., Jamieson, A. and Russell, N. (1987) Afferent C-fibre and A-delta activity in models of inflammation. British Journal of Pharmacology 90, 164-169.
Hein, A., Stutzman, D., Bland, S., Barrientos, R., Watkins, L. and Rudy, J. (2007) Prostaglandins are necessary and sufficient to induce contextual fear learning impairments after interleukin-1 beta injections into the dorsal hippocampus. Neuroscience 150, 754-763.
Henry, M.A. and Hargreaves, K.M. (2007) Peripheral mechanisms of odontogenic pain. Dental Clinics of North America 51, 19-44.
Hoot, M.R., Sim-Selley, L.J., Poklis, J.L., Abdullah, R.A., Scoggins, K.L., Selley, D.E. (2010) Chronic constriction injury reduces cannabinoid receptor 1 activity in the rostral anterior cingulate cortex of mice. Brain Research 139, 18-25.
Hu, Y., Yang, J., Wang, Y. and Li, W. (2010) Amitriptyline rather than lornoxicam ameliorates neuropathic pain-induced deficits in abilities of spatial learning and memory. European Journal of Anaesthesiology 27, 162-168.
Ji, G., Sun. H., Fu, Y., Li, Z., Pais-Vieira, M. and Galhardo, V. (2010) Cognitive impairment in pain through amygdala-driven prefrontal cortical deactivation. The Journal of Neuroscience 30, 5451-5464.
Ji, R.R., Kohno, T., Moore, K.A. and Woolf, C.J. (2003) Central sensitization and LTP: do pain and memory share similar mechanisms? Trends in Neurosciences 26, 696-705.
Julius, D. and Basbaum, A.I. (2001) Molecular mechanisms of nociception. Nature 413, 203-210.
Katsuki. H., Nakai, S., Hirai, Y., Akaji, K., Kiso, Y. and Satoh, M. (1990) Interleukin-1β inhibits long-term potentiation in the CA3 region of mouse hippocampal slices. European Journal of Pharmacology 181, 323–326.
Kozlovsky N, Matar MA, Kaplan Z, Kotler M, Zohar J, Cohen H. (2007) Long-term down-regulation of BDNF mRNA in rat hippocampal CA1 subregion correlates with PTSD-like behavioural stress response. International Journal of Neuropsychopharmacology 10, 741-58.
Khairova RA, Machado-Vieira R, Du J, Manji HK. (2009) A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder. International Journal of Neuropsychopharmacology 12, 561-78.
Kuchinad, A., Schweinhardt, P., Seminowicz, D.A., Wood, P.B., Chizh, B.A. and Bushnell, M.C. (2007) Accelerated brain gray matter loss in fibromyalgia patients: premature aging of the brain? The Journal of Neuroscience 27, 4004-4007.
Kuhajda, M.C., Thorn, B.E., Klinger, M.R. and Rubin, N.J. (2002) The effect of headache pain on attention (encoding) and memory (recognition). Pain 97, 213-221.
Kunugi, H., Hori, H., Adachi, N. and Numakawa, T. (2010) Interface between hypothalamic pituitary adrenal axis and brain derived neurotrophic factor in depression. Psychiatry and Clinical Neurosciences 64, 447-459.
Li, Y., Peng, S., Wan, C., Cao, L. and Li, Y. (2005) Chronic pain impairs spatial learning and memory ability and down-regulates Bcl-2 and BDNF mRNA expression in hippocampus of neonatal rats. Zhonghua er ke za zhi. Chinese journal of pediatrics 43, 444-448.
Lucca, U., Tettamanti, M., Forloni, G. and Spagnoli, A. (1994) Nonsteroidal antiinflammatory drug use in Alzheimer's disease. Biological Psychiatry 36, 854-856.
McNamara, C.R., Mandel-Brehm, J., Bautista, D.M., Siemens, J., Deranian, K.L. and Zhao, M. (2007) TRPA1 mediates formalin-induced pain. Proceedings of the National Academy of Sciences USA 104, 13525-13530.
Morris, R.G., Garrud, P., Rawlins, J.N. and O'Keefe, J. (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297, 681-683.
Moure-Leite, F., Ramos-Jorge, J., Ramos-Jorge, M., Paiva, S., Vale, M. and Pordeus, I. (2011) Impact of dental pain on daily living of five-year-old Brazilian preschool children: prevalence and associated factors. European Archives of Paediatric Dentistry 12, 293-297.
Okiji, T., Morita, I., Sunada, I. and Murota, S. (1989) Involvement of arachidonic acid metabolites in increases in vascular permeability in experimental dental pulpal inflammation in the rat. Archives of Oral Biology 34, 523-528.
Petrosino, S., Palazzo, E., de Novellis, V., Bisogno, T., Rossi, F., Maione, S. (2007) Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats. Neuropharmacology 52, 415-422.
Prasad, K.N., Cole, W.C. and Prasad, K.C. (2002) Risk factors for Alzheimer’s disease: role of multiple antioxidants, non-steroidal anti-inflammatory and cholinergic agents alone or in combination in prevention and treatment. The Journal of the American College of Nutrition 21, 506-522.
Raoof, M., Abbasnejad, M., Amirkhosravi, L., Ebrahimnejad, H. and Raoof, R. (2013) A modification of a previous model for inflammatory tooth pain: Effects of different capsaicin and formalin concentrations and ibuprofen. Journal of Oral Health and Oral Epidemiology 1, 7-15.
Ren, W.J., Liu, Y., Zhou, L.J., Li, W., Zhong, Y., Pang, R.P. (2011) Peripheral nerve injury leads to working memory deficits and dysfunction of the hippocampus by upregulation of TNF-α in rodents. Neuropsychopharmacology 36, 979-992.
Rich, J.B., Rasmusson, D., Folstein, M., Carson, K., Kawas, C. and Brandt, J. (1995) Nonsteroidal anti-inflammatory drugs in Alzheimer's disease. Neurology 45, 51-55.
Riedel, G. and Davies, S. (2005) Cannabinoid function in learning, memory and plasticity. Handbook of Experimental Pharmacology 168, 445-77.
Schmidt-Wilcke, T., Luerding, R., Weigand, T., Jürgens, T., Schuierer, G., Leinisch, E. and Bogdahn, U. (2007) Striatal grey matter increase in patients suffering from fibromyalgia–a voxel-based morphometry study. Pain 132, 109-116.
Shetty N1, Patil AK, Ganeshkar SV, Hegde S. (2013) Comparison of the effects of ibuprofen and acetaminophen on PGE2 levels in the GCF during orthodontic tooth movement: a human study. Progress in Orthodontics 17, 14-6.
Southall MD1, Li T, Gharibova LS, Pei Y, Nicol GD, Travers JB. (2003) Activation of epidermal vanilloid receptor-1 induces release of proinflammatory mediators in human keratinocytes. Journal of Pharmacology and Experimental Therapeutics 304, 217-222.
Squire LR. (1992) Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychological Review 99, 195-231.
Valfrè, W., Rainero, I., Bergui, M. and Pinessi, L. (2008) Based Morphometry Reveals Gray Matter Abnormalities in Migraine. Headache 48, 109-117.
Watkins, L.R., Milligan, E.D. and Maier, S.F. (2001) Spinal cord glia: new players in pain. Pain 93, 201-205.
Webster, J.I. and Sternberg, E.M. (2004) Role of the hypothalamic-pituitary-adrenal axis, glucocorticoids and glucocorticoid receptors in toxic sequelae of exposure to bacterial and viral products. Journal of Endocrinology 181, 207-221.
Woolf, C.J. and Salter, M.W. (2000) Neuronal plasticity: increasing the gain in pain. Science 288, 1765-1768.
Zhao, X.Y., Liu, M.G., Yuan, D.L., Wang, Y., He, Y. and Wang, D.D. (2009) Nociception-induced spatial and temporal plasticity of synaptic connection and function in the hippocampal formation of rats: a multi-electrode array recording. Molecular Pain 5, 55-78.
Zhuo, M. (2007) A synaptic model for pain: long-term potentiation in the anterior cingulate cortex. Molecules and Cells 23, 259-271.