Analgesic effects of mambalgin peptide inhibitors of acid-sensing ion channels in inflammatory and neuropathic pain.
Mambalgins are 57-amino acid peptides isolated from snake venom that evoke naloxone-resistant analgesia after local (intraplantar) and central (intrathecal) injections through inhibition of particular subtypes of acid-sensing ion channels (ASICs). We now show that mambalgins also have an opioid-independent effect on both thermal and mechanical inflammatory pain after systemic intravenous (i.v.) administration and are effective against neuropathic pain. By combining the use of knockdown and knockout animals, we show the critical involvement of peripheral ASIC1b-containing channels, along with a contribution of ASIC1a-containing channels, in the i.v. effects of these peptides against inflammatory pain. The potent analgesic effect on neuropathic pain involves 2 different mechanisms depending on the route of administration, a naloxone-insensitive and ASIC1a-independent effect associated with i.v. injection and an ASIC1a-dependent and partially naloxone-sensitive effect associated with intrathecal injection. These data further support the role of peripheral and central ASIC1-containing channels in pain, demonstrate their participation in neuropathic pain, and highlight differences in the repertoire of channels involved in different pain conditions. They also strengthen the therapeutic potential of mambalgin peptides that are active in a broader range of experimental pain models and through i.v. systemic delivery.
CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, Valbonne, France Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France LabEx Ion Channel Science and Therapeutics, UMR 7275, Valbonne, France Clermont Université, Université d'Auvergne, Neuro-Dol, Clermont-Ferrand, France Inserm, U 1107, Clermont-Ferrand, France CHU Clermontferrand, Service de Pharmacologie, Clermont-Ferrand, France.
Sylvie
S
Diochot
Abdelkrim
A
Alloui
Précillia
P
Rodrigues
Mélodie
M
Dauvois
Valérie
V
Friend
Youssef
Y
Aissouni
Alain
A
Eschalier
Eric
E
Lingueglia
Anne
A
Baron
D062646:Acid Sensing Ion Channel Blockers / Q000627:therapeutic use*; D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D004546:Elapid Venoms / Q000627:therapeutic use*; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009437:Neuralgia / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000627:therapeutic use*; D051381:Rats; D016896:Treatment Outcome; D014982:Xenopus laevis
D062646:Acid Sensing Ion Channel Blockers; D000700:Analgesics; D004546:Elapid Venoms; D010455:Peptides; C576673:mambalgin-1, Dendroaspis polylepis