title: Non-opioid nociceptive activity of human dynorphin mutants that cause neurodegenerative disorder spinocerebellar ataxia type 23.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Biosciences, Division of Biological Research on Drug Dependence, Uppsala University, Uppsala, Sweden. hiroyuki.watanabe@farmbio.uu.se
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Watanabe
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Mizoguchi
authors.forename: Dineke S
authors.initials: DS
authors.lastname: Verbeek
authors.forename: Alexander
authors.initials: A
authors.lastname: Kuzmin
authors.forename: Fred
authors.initials: F
authors.lastname: Nyberg
authors.forename: Oleg
authors.initials: O
authors.lastname: Krishtal
authors.forename: Shinobu
authors.initials: S
authors.lastname: Sakurada
authors.forename: Georgy
authors.initials: G
authors.lastname: Bakalkin
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004399:Dynorphins / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000494:pharmacology; D020125:Mutation, Missense; D009270:Naloxone / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D011957:Receptors, Opioid / Q000378:metabolism; D018039:Receptors, Tachykinin / Q000378:metabolism; D013132:Spinocerebellar Degenerations / Q000235:genetics*
chemical_list: D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D011957:Receptors, Opioid; D018039:Receptors, Tachykinin; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D009270:Naloxone; D016291:Dizocilpine Maleate; D004399:Dynorphins; D009020:Morphine