PMID- 22531488
OWN - NLM
STAT- MEDLINE
DCOM- 20121119
LR  - 20131121
IS  - 1873-5169 (Electronic)
IS  - 0196-9781 (Linking)
VI  - 35
IP  - 2
DP  - 2012 Jun
TI  - Non-opioid nociceptive activity of human dynorphin mutants that cause 
      neurodegenerative disorder spinocerebellar ataxia type 23.
PG  - 306-10
LID - 10.1016/j.peptides.2012.04.006 [doi]
AB  - We previously identified four missense mutations in the prodynorphin gene that 
      cause human neurodegenerative disorder spinocerebellar ataxia type 23 (SCA23). 
      Three mutations substitute Leu(5), Arg(6), and Arg(9) 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.; 0.1-1 mg/kg) or MK-801, an NMDA ion 
      channel blocker (i.t. co-administration; 5-7.5 nmol). CP-99,994, a tachykinin NK1 
      receptor antagonist (i.t. co-administration; 2 nmol) and naloxone (i.p.; 5 mg/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-opioid excitatory 
      activities of Dyn A mutants may underlie in part development of SCA23.
CI  - Copyright (c) 2012 Elsevier Inc. All rights reserved.
FAU - Watanabe, Hiroyuki
AU  - Watanabe H
AD  - Department of Pharmaceutical Biosciences, Division of Biological Research on Drug 
      Dependence, Uppsala University, Uppsala, Sweden. hiroyuki.watanabe@farmbio.uu.se
FAU - Mizoguchi, Hirokazu
AU  - Mizoguchi H
FAU - Verbeek, Dineke S
AU  - Verbeek DS
FAU - Kuzmin, Alexander
AU  - Kuzmin A
FAU - Nyberg, Fred
AU  - Nyberg F
FAU - Krishtal, Oleg
AU  - Krishtal O
FAU - Sakurada, Shinobu
AU  - Sakurada S
FAU - Bakalkin, Georgy
AU  - Bakalkin G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120417
PL  - United States
TA  - Peptides
JT  - Peptides
JID - 8008690
RN  - 0 (Piperidines)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (Receptors, Opioid)
RN  - 0 (Receptors, Tachykinin)
RN  - 136982-36-0 (3-(2-methoxybenzylamino)-2-phenylpiperidine)
RN  - 36B82AMQ7N (Naloxone)
RN  - 6LR8C1B66Q (Dizocilpine Maleate)
RN  - 74913-18-1 (Dynorphins)
RN  - 76I7G6D29C (Morphine)
RN  - Spinocerebellar ataxia 23
SB  - IM
MH  - Amino Acid Substitution
MH  - Animals
MH  - Behavior, Animal/drug effects
MH  - Dizocilpine Maleate/pharmacology
MH  - Dynorphins/genetics/*pharmacology
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred ICR
MH  - Morphine/pharmacology
MH  - Mutation, Missense
MH  - Naloxone/pharmacology
MH  - Piperidines/pharmacology
MH  - Receptors, N-Methyl-D-Aspartate/*metabolism
MH  - Receptors, Opioid/metabolism
MH  - Receptors, Tachykinin/metabolism
MH  - Spinocerebellar Degenerations/*genetics
EDAT- 2012/04/26 06:00
MHDA- 2012/12/10 06:00
CRDT- 2012/04/26 06:00
PHST- 2012/03/09 00:00 [received]
PHST- 2012/04/10 00:00 [revised]
PHST- 2012/04/10 00:00 [accepted]
PHST- 2012/04/26 06:00 [entrez]
PHST- 2012/04/26 06:00 [pubmed]
PHST- 2012/12/10 06:00 [medline]
AID - S0196-9781(12)00188-X [pii]
AID - 10.1016/j.peptides.2012.04.006 [doi]
PST - ppublish
SO  - Peptides. 2012 Jun;35(2):306-10. doi: 10.1016/j.peptides.2012.04.006. Epub 2012 
      Apr 17.