Abstract
The activation of presynaptic histamine 3 (H3) receptors inhibits the release of histamine and other neurotransmitters from central nervous system neurons. Rat brain mast cells (MCs) release histamine and 5-hydroxytryptamine (5-HT) in response to neuropeptides and neurotransmitters secreted from adjacent neurons. Dura MCs also degranulate in response to antidromic trigeminal nerve stimulation and with acute psychological stress. Such findings have implicated brain MCs in certain neuroinflammatory disorders, such as migraines. We investigated the ultrastructural appearance of control and stimulated thalamic/hypothalamic (brain) MCs before and after treatment with the H3 receptor agonistNα-methylhistamine (Nα-mH) and the H3 receptor antagonist thioperamide (Th). Ultrastructural investigation of brain MCs stimulated with compound 48/80 revealed extensive intragranular changes that paralleled 5-HT secretion but without degranulation by exocytosis typical of connective tissue MCs. Nα-mH significantly reduced these morphological changes, as well as 5-HT release from brain MCs and neurons stimulated with KCl; conversely, Th augmented both histamine and 5-HT release from brain neurons and MCs. Neither Nα-mH nor Th had any effect on peritoneal MCs. Simultaneous addition of both drugs largely antagonized each other’s effects on brain MC activation and 5-HT secretion. Ultrastructural observations and lack of lactic dehydrogenase release in the perfusate excluded any cytotoxic effect. The ability of H3 agonists to inhibit brain MC activation, as well as secretion of 5-HT from both brain MCs and neurons, may be useful in the management of migraines.
Footnotes
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Send reprint requests to: T. C. Theoharides, Ph.D., M.D., Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111. E-mail: ttheoharides{at}infonet.tufts.edu
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↵1 This work was supported by a grant from Kos Pharmaceuticals (Miami, FL).
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↵2 The possible therapeutic use of H3 agonists in the treatment of migraines is covered by U.S. Patent 5,855,884 awarded to T.C.T.
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↵3 Present address: Department of Neurology, Medical Academy, Lodz 90153, Poland.
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↵4 Present address: Department of Neurosurgery, Cornell Medical College, Cornell, NY 10021.
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↵5 Present address: Department of Surgery, New England Medical Center, Boston, MA 02111.
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↵6 Present address: Department of Emergency Medicine, Langley Air Force Base, Hampton, VA 23665.
- Abbreviations:
- CNS
- central nervous system
- C48/80
- compound 48/80
- CTMC
- connective tissue mast cell
- H3
- histamine 3
- 5-HT
- 5-hydroxytryptamine (serotonin)
- IMI
- imipramine
- KRB
- Krebs-Ringer bicarbonate buffer
- LDH
- lactic dehydrogenase
- MC
- mast cell
- mH
- methylhistamine
- MS
- multiple sclerosis
- Nα-mH
- Nα-methylhistamine
- RIA
- radioimmunoassay
- Th
- thioperamide
- TNF
- tumor necrosis factor
- Received November 3, 1998.
- Accepted April 29, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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