Metallopeptidase inhibition potentiates bradykinin-induced hyperalgesia.

Abstract:

:The neuropeptide bradykinin (BK) sensitizes nociceptor activation following its release in response to inflammatory injury. Thereafter, the bioactivity of bradykinin is controlled by the enzymatic activities of circulating peptidases. One such enzyme, the metalloendopeptidase EC3.4.24.15 (EP24.15), is co-expressed with bradykinin receptors in primary afferent neurons. In this study, using approaches encompassing pharmacology, biochemistry, cell biology, and behavioral animal models, we identified a crucial role for EP24.15 and the closely related EP24.16 in modulating bradykinin-mediated hyperalgesia. Pharmacological analyses indicated that EP24.15 and EP24.16 inhibition significantly enhances bradykinin type-2 receptor activation by bradykinin in primary trigeminal ganglia cultures. In addition, bradykinin-induced sensitization of TRPV1 activation was increased in the presence of the EP24.15/16 inhibitor JA-2. Furthermore, behavioral analyses illustrated a significant dose-response relationship between JA-2 and bradykinin-mediated thermal hyperalgesia. These results indicate an important physiological role for the metallopeptidases EP24.15 and EP24.16 in regulating bradykinin-mediated sensitization of primary afferent nociceptors.

journal_name

Pain

journal_title

Pain

authors

Gomez R,Por ED,Berg KA,Clarke WP,Glucksman MJ,Jeske NA

doi

10.1016/j.pain.2011.02.044

subject

Has Abstract

pub_date

2011-07-01 00:00:00

pages

1548-1554

issue

7

eissn

0304-3959

issn

1872-6623

pii

00006396-201107000-00019

journal_volume

152

pub_type

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