Arizona Health Sciences

Blockade of non-opioid excitatory effects of spinal dynorphin A at bradykinin receptors.

TitleBlockade of non-opioid excitatory effects of spinal dynorphin A at bradykinin receptors.
Publication TypeJournal Article
Year of Publication2015
AuthorsLee YSun, Hall SM, Ramos-Colon C, Remesic M, Rankin D, Vanderah TW, Porreca F, Lai J, Hruby VJ
JournalReceptors Clin Investig
Volume2
Issue1
Date Published2015
ISSN2330-0558
Abstract

Dynorphin A (Dyn A) is an endogenous opioid ligand that possesses neuroinhibitory (antinociceptive) effects via μ, δ, and κ opioid receptors. However, under chronic pain conditions, up-regulated spinal Dyn A can also interact with bradykinin receptors (BRs) to promote hyperalgesia through a neuroexcitatory(pronociceptive) effect. These excitatory effects cannot be blocked by an opioid antagonist, and thus are non-opioid in nature. On the basis of the structural dissimilarity between Dyn A and endogenous BR ligands, bradykinin(BK) and kallidin (KD), Dyn A's interaction with BRs could not be predicted, and provided an opportunity to identify a novel potential neuroexcitatory target. Systematic structure-activity relationship (SAR) studies discovered a minimum pharmacophore of Dyn A, [des-Arg(7)]-Dyn A-(4-11) LYS1044 for antagonist activity at the BRs, along with insights into the key structural features for BRs recognition, i.e., amphipathicity. The des-Tyr fragment of dynorphin does not bind to opioid receptors. Intrathecal administration of des-Tyr dynorphin produces hyperalgesia reminiscent of behaviors seen in peripheral n europathic pain models and at higher doses, neurotoxicity. Our lead ligand LYS1044 negatively modulated Dyn A-(2-13)-induced neuroexcitatory effects in naïve animals and blocked mechanical hypersensitivity and thermal hyperalgesia in a dose-dependent manner in animals with experimental neuropathic pain. Based on these results, ligand LYS1044 might prevent abnormal pain states by blocking the neuroexcitatory effects of increased levels of Dyn A that are seen in experimental models of neuropathic pain and that likely promote excitation mediated by BRs in the spinal cord.

DOI10.14800/rci.517
Alternate JournalReceptors Clin Investig
PubMed ID26221618
PubMed Central IDPMC4515361
Grant ListP01 DA006284 / DA / NIDA NIH HHS / United States
R01 DA013449 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
Yeon Sun Lee, Ph.D.
Frank Porreca, Ph.D.
Todd Vanderah, Ph.D.