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Journal Article

Journal Article

Non-opioid nociceptive activity of human dynorphin mutants that cause neurodegenerative disorder spinocerebellar ataxia type 23  [2012]

Watanabe, Hiroyuki; Mizoguchi, Hirokazu; Verbeek, Dineke S.; Kuzmin, Alexander; et al.

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We previously identified four missense mutations in the prodynorphin gene that cause human neurodegenerative disorder spinocerebellar ataxia type 23 (SCA23). Three mutations substitute Leu⁵, Arg⁶, and Arg⁹ to Ser (L5S), Trp (R6W) and Cys (R9C) in dynorphin A(1–17) (Dyn A), a peptide with both opioid activities and non-opioid neurodegenerative actions. It has been reported that Dyn A administered intrathecally (i.t.) in femtomolar doses into mice produces nociceptive behaviors consisting of hindlimb scratching along with biting and licking of the hindpaw and tail (SBL responses) through a non-opioid mechanism. We here evaluated the potential of the three mutant peptides to produce similar behaviors. Compared to the wild type (WT)-peptide, the relative potency of Dyn A R6W, L5S and R9C peptides for SBL responses was 50-, 33- and 2-fold higher, and Dyn A R6W and L5S induced the SBL responses at a 10–30-fold lower doses. Dyn A R6W was the most potent peptide. The SBL responses induced by Dyn A R6W were dose dependently inhibited by morphine (i.p.; 0.1–1mg/kg) or MK-801, an NMDA ion channel blocker (i.t. co-administration; 5–7.5nmol). CP-99,994, a tachykinin NK1 receptor antagonist (i.t. co-administration; 2nmol) and naloxone (i.p.; 5mg/kg) failed to block effects of Dyn A R6W. Thus, similarly to Dyn A WT, the SBL responses induced by Dyn A R6W may involve the NMDA receptor but are not mediated through the opioid and tachykinin NK1 receptors. Enhanced non-opioi
d excitatory activities of Dyn A mutants may underlie in part development of SCA23.

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Bibliographic information

Language:
English
Type:
Journal Article
In AGRIS since:
2016
Volume:
35
Issue:
2
Start Page:
306
End Page:
310
Publisher:
Elsevier Inc.
All titles:
" Non-opioid nociceptive activity of human dynorphin mutants that cause neurodegenerative disorder spinocerebellar ataxia type 23 "

From the journal

Peptides

ISSN : 0196-9781