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

Abstract

Dynorphin A (Dyn A) is an endogenous opioid peptide that produces neuroinhibitory (antinociceptive) effects via m, d, and k 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. Considering the structural dissimilarity between Dyn A and endogenous BR ligands, bradykinin (BK) and kallidin (KD), this interaction could not be predicted, and provided an opportunity to discover a novel potential neuroexcitatory target. Systematic structure-activity relationship (SAR) studies discovered a minimum pharmacophore of Dyn A, [des-Arg⁷]-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 neuropathic pain models and at higher doses, neurotoxicity. Our lead ligand LYS1044 blocked Dyn A-(2-13)-induced neuroexcitatory effects in naïve animals and reversed thermal hyperalgesia and mechanical hypersensitivity in a dose-dependent manner in animals with experimental neuropathic pain. Based on these results, ligand LYS1044 might inhibit abnormal pain states by blocking the neuroexcitatory effects of enhanced 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.