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Dissertation Information for Kirk W. Johnson

NAME:
- Kirk W. Johnson

DEGREE:
- Ph.D.

DISCIPLINE:
- Medical Neurobiology

SCHOOL:
- Indiana University (USA) (2005)

ADVISORS:
- Anantha Shekhar

COMMITTEE MEMBERS:
- Lee A. Phebus
- Michael R. Vasko
- Charles R. Goodlett

MPACT Status: Incomplete - Not_Inspected

Title: Characterization of the role of serotonin receptor subtypes (5-HT(1) and 5-HT(2)) and nitric oxide in Guinea pig dural plasma protein extravasation

Abstract: Neurogenic inflammation of the dura mater has been proposed to be associated with migraine pain. Dural plasma protein extravasation (PPE), one component of neurogenic inflammation, can be induced and quantified in guinea pigs following electrical stimulation of the trigeminal nerve. As such, dural PPE has been utilized as an animal model of migraine. Current acute and prophylactic migraine therapies include non-selective 5-HT 1 agonists and 5-HT 2 antagonists, respectively. Studies were completed to characterize the 5-HT1 receptor subtype(s) involved in the inhibition of trigeminal stimulation-induced dural PPE by 5-HT 1 agonists (LY302148, LY306258, LY334370, L-694,247, CP-122,288, sumatriptan, dihydroergotamine, zolmitriptan, rizatriptan and naratriptan). Correlational analysis revealed that potency in the PPE model following intravenous administration of the compounds correlated best with the compounds' binding affinity and functional agonist activity at the human cloned 5-HT 1F receptor. Further, the inhibitory effect of a selective 5-HT 1F agonist (LY397584) in the PPE model was reversed following pretreatment with a selective 5-HT 1F antagonist (LY374291). Two pharmacological agents that induce migraine attacks in individuals with a history of migraine, meta-chlorophenylpiperazine (mCPP) and the nitric oxide donor nitroglycerin, were both shown to induce dural PPE in guinea pigs. The mCPP-induced dural PPE was blocked by pretreatment with non-selective 5-HT 2 antagonists (methysergide, LY53857, LY215840), a selective 5-HT 2B antagonist (LY202146), but not by a potent 5-HT 2A/2C antagonist (LY310898). The peripherally restricted 5-HT 2 receptor antagonist xylamidine and the 5-HT 1 receptor agonist sumatriptan also blocked mCPP-induced dural PPE. However, LY202146 did not inhibit trigeminal stimulationinduced PPE at doses 100 times higher than necessary to inhibit mCPP-induced PPE. The nitric oxide (NO) synthase inhibitor, L-NAME, also blocked dural extravasation due to mCPP. The inhibitory effect of L-NAME was overcome by co-administration of an excess of L-arginine, the substrate for production of NO by nitric oxide synthase. Finally, L-NAME did not inhibit trigeminal stimulation-induced PPE. These data suggest the inhibitory effects of 5-HT 1 agonists in the trigeminal stimulation-induced PPE model are via activation of 5-HT 1F receptors. These data also suggest that activation of peripheral 5-HT 2B receptors initiates the release of nitric oxide, which could induce the subsequent neurogenic inflammation and dural plasma protein extravasation.

MPACT Scores for Kirk W. Johnson

A = 0
C = 0
A+C = 0
T = 0
G = 0
W = 0
TD = 0
TA = 0
calculated 2010-09-27 16:39:52

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