Research Interests
Primary Research Interests: Neuroimmunologic regulation of Pain and Stress Hormones. Our laboratory studies pain transmission with a special emphasis on the influence of gender and immunology. The goal is to understand painful conditions, such as fibromyalgia syndrome, that occur more frequently in females and are exacerbated by stress. Our focus is on mast cells, immune cells that enter the CNS in response to stress and certain reproductive hormones.
Mast cells are localized in the thalamus, an area important in sensory transmission, including pain. Mast cells are more abundant in specific areas of the female than the male thalamus. We found that interfering with the degranulation of mast cells by the central injection of cromolyn, a mast cell stabilizer, blocks the acquisition of appropriate breeding behaviors in female mice, perhaps by an influence on sensory transmission.
The classic increase in HPA activity produced by restraint stress in mice is prolonged by the central injection of cromolyn prior to restraint. This suggests that one role of mast cells is to protect against excessive and prolonged stress responses.
Chronic stress increases the number of mast cells in the thalamus, suggesting that they become increasingly important in these circumstances. Our studies will determine (1) the biochemical signals that recruit mast cells to the brain, (2) the anatomical distribution of mast cells in response to pain and stress, and (3) the influence of centrally located mast cells on the regulation of pain and stress responses.
Selected Publications
(For a comprehensive list of Dr. Larson's recent publications, refer to PubMed, a service provided by the National Library of Medicine.)
Russell, I. Jon and Alice A. Larson: Neurophysiopathogenesis of fibromyalgia syndrome: a unified hypothesis. Rheum Dis Clin N Am 35: 421-435, 2009.
Alice A. Larson and Katalin J. Kovacs: Fibromyalgia, Mechanisms and Treatment, in Treatment of Neuropathic Pain, Schmidt, R.F, & Willis, W.D., Editors, Encyclopedic Reference of Pain. Springer, Berlin Heidelberg New York, 2006, 2010. ISBN-13: 9783540439578
Larson, Alice A. Mark J. Thomas Alex McElhose and Katalin J. Kovács: Spontaneous locomotor activity correlates with the degranulation of mast cells in the meninges rather than in the thalamus: Disruptive effect of cocaine. Brain Research 1395: 30-37, 2011.
Laughlin, Tinna M., Alice A. Larson, George L. Wilcox: Mechanisms of Induction of Persistent Nociception by Dynorphin. Journal of Pharmacology and Experimental Therapeutics 299(1): 6-11, 2001.
Larson, Alice A. and Katalin J. Kovács: Nocicieptive Aspects of Fibromyalgia (Invited Review). Current Pain and Headache Reports 5(4): 338-346, Aug 2001.
Kovács, Katalin J., Yongjiu Cai, and Alice A. Larson: Neuronal nitric oxide synthase (nNOS) mRNA is downregulated and constitutive NOS enzymatic activity decreased in thoracic dorsal root ganglia and spinal cord by a substance P N-terminal metabolite. European Journal of Neuroscience 14(4): 577-584, 2001.
Velázquez, Ruben L., Kenneth E. McCarson, Yongjiu Cai, Katalin J. Kovács, Qiuying Shi, Maria Evensjo, and Alice A. Larson: Up-regulation of neurokinin-1 receptor expression in rat spinal cord by an N-terminal metabolite of substance P. European Journal of Neuroscience 16: 229-241, 2002.
Fang, Ming, Katalin J. Kovács, Lauralei L. Fisher, and Alice A. Larson: Thrombin inhibits NMDA-mediated nociceptive activity in the mouse: Possible mediation by endothelin. Journal of Physiology 549(3) 903-917, 2003.
Tien, Duc, Peter T. Ohara, Alice A. Larson, and Luc Jasmin: Vagal afferents are necessary for the establishment but not the maintenance of kainic acid-induced hyperalgesia in mice. Pain 102: 39-49, 2003.
Taiwo, Oludare B., Katalin J. Kovács, Lauren C. Sperry, and Alice A. Larson: Naloxone-induced morphine withdrawal increases the number and degranulation of mast cells in the thalamus of the mouse. Neuropharmacology 46: 824-835, 2004.
Kehl, Lois J., Katalin J. Kovács, Alice A. Larson: Tolerance develops to the effect of lipopolysaccharides on movement-evoked hyperalgesia when administered chronically by a systemic but not an intrathecal route. Pain 111: 104-115 2004.
Taiwo, Oludare B., Katalin J. Kovács, Yanxi Sun, Alice A. Larson: Unilateral spinal nerve ligation leads to an asymmetrical distribution of mast cells in the thalamus of female but male mice, Pain 114: 131-140, 2005.
Lason, Alice A. and Katalin J. Kovács: Fibromyalgia, Mechanisms and Treatment, in Treatment of Neuropathic Pain, Schmidt, R.F., & Willis, W.D., Editors, Encyclopedic Reference of Pain. Springer, Berlin Heidelberg New York 2006, on-line 2007.
Kovács, Katalin J. and Alice A. Larson: Mast cells aggregate in the anogenital region of somatotopically organized thalamic nuclei during estrus in female mice. Brain Research 1114: 85-97, 2006.
Taiwo Oludare B., I. Jon Russell, Emmanuel Mignot, L. Lin, Joel E. Michalek, Wanda Haynes, Y. Xiao, J. M. Zeitzer, Alice A. Larson. Normal cerebrospinal fluid levels of hypocretin-1 (orexin A) in patients with fibromyalgia syndrome are significantly increased by treatment with tizanidine. Sleep Med. Mar 16: 17369087, 2007.
Kovacs, Katalin J., Jonathan C. Papic and Alice A. Larson: Movement- evoked hyperalgesia induced by lipopolysaccharides is not suppressed by glucocorticoids. Pain136: 75-84, 2008.
Current Funding
“Thalamic Mast Cells Inhibit HPA Activity”, Academic Health Center at the University of Minnesota
Honors and Awards
National Institute of Mental Health (NIMH) Study Section Member, Behavioral Neurobiology Subcommittee, 1988–1992
National Institute on Drug Abuse (NIDA) Career Development Award, 1988–1993
SmithKline Beecham Award for Research Excellence, 1995
Associate Editor for the Journal of Pharmacology and Experimental Therapeutics, 1999–2000
Scientific Advisory Board Member for the American Fibromyalgia Association Foundation (AFSA), 2000–present
Graduate Students
Nelson L. Dalo, D.V.M. (M.S. 1984, Veterinary Physiology and Pharmacology), currently an Associate Professor of Pharmacology
James Madl, D.V.M. (Ph.D. 1987, Veterinary Physiology and Pharmacology), currently Assoc Professor at Colorado State University
Stephen Skilling, D.V.M. (Ph.D. 1989, Veterinary Biology) currently a practicing veterinarian in Burnsville, MN
Carl Hornfelt (M.S. 1990; Ph.D. 1998, Veterinary Biology) currently a researcher at Medtronics
Sun Xiaofeng, M.S. 1990; Ph.D. 1993, Veterinary Biology) currently a researcher at Mayo Clinic
Julie Kreeger, D.V.M., M.S., Ph.D. 1995, Veterinary Biology) currently a researcher at the National Black-Footed Ferret Conservation Center, Laramie WY
Virginia Geottl (D.V.M./Ph.D. 1996, Neuroscience, University of Minnesota). Currently a Research Associate at The Ohio State University.
Susan L. Giovengo D.V.M. (Ph.D. 1997, Veterinary Biomedical Sciences, University of Minnesota) Currently at The Proctor and Gamble Co., Mason OH
Ruben Velazquez (M.D./Ph.D. 1998, Neuroscience, University of Minnesota). Currently a physician specializing in ear, nose and throat in Puerto Rico.
