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Discovery of amphipathic dynorphin A analogues to inhibit the neuroexcitatory effects of dynorphin A through bradykinin receptors in the spinal cord

Significance statement

 

There are very few current treatments for chronic neuropathic pain and those that are available are often ineffective, have numerous toxicities and can lead to dependence, addiction and low quality of life. This study shows the ability of LYS1044 ([des-Arg7]-DynA-(4-11)), our lead ligand, to reverse abnormal pain states by blocking the neuroexcitatory effects of up-regulated level of Dyn A via bradykinin receptors. The ligand blocks [Des-Tyr1]-Dyn A-induced hyperalgesic effects and motor impairment in naïve animals and inhibits thermal hyperalgesia and mechanical hypersensitivity in a dose-dependent manner in nerve-injured animals. Importantly, the ability of LYS1044 is limited to the CNS and thus can avoid serious cardiovascular effects caused by blocking peripheral bradykinin receptors. Overall, this study suggests that we have discovered an endogenous ligand for the central bradykinin receptors and thus a novel approach to the treatment of chronic neuropathic pain without the toxicities associated with current treatments for these maladies.

Figure Legend: Chronic pain, nerve injury and inflammation often result in the up regulation of Dynorphin A in the spinal column neurotransmitter pathway to the brain.  We have discovered a novel mechanism of neurotransmission related to pain in which the bradykinin receptors are upregulated and Dynorphin A peptides have neuroexcitatory effects that result in hyperalgesia.  We also discovered Dynorphin A fragment analogues that inhibit these neuroexcitatory effects leading to antihyperalgesia in vivo.  These findings open up a new approach to the treatment of pain.

Discovery of Amphipathic Dynorphin A Analogues to Inhibit the Neuroexcitatory Effects of Dynorphin A through Bradykinin Receptors in the Spinal Cord. Global Medical Discovery

 

 

 

 

Journal Reference

Lee YS, Muthu D, Hall SM, Ramos-Colon C, Rankin D, Hu J, Sandweiss AJ, De Felice M, Xie JY, Vanderah TW, Porreca F, Lai J, Hruby VJ. J Am Chem Soc. 2014 May 7;136(18):6608-16.

Department of Chemistry and Biochemistry and ‡Department of Pharmacology, The University of Arizona , Tucson, Arizona 85721, United States.

Abstract

We hypothesized that under chronic pain conditions, up-regulated dynorphin A (Dyn A) interacts with bradykinin receptors (BRs) in the spinal cord to promote hyperalgesia through an excitatory effect, which is opposite to the well-known inhibitory effect of opioid receptors. Considering the structural dissimilarity between dynorphin A and endogenous BR ligands, bradykinin (BK) and kallidin (KD), this interaction could not be predicted, but it allowed us to discover a potential neuroexcitatory target. Well-known BR ligands, BK, [des-Arg(10), Leu(9)]-kallidin (DALKD), and HOE140 showed different binding profiles at rat brain BRs than that previously reported. These results suggest that neuronal BRs in the rat central nervous system (CNS) may be pharmacologically distinct from those previously defined in non-neuronal tissues. Systematic structure-activity relationship (SAR) study at the rat brain BRs was performed, and as a result, a new key structural feature of dynorphin A for BR recognition was identified: amphipathicity. NMR studies of two lead ligands, Dyn A-(4-11) 7 and [des-Arg(7)]-Dyn A-(4-11) 14, which showed the same high binding affinity, confirmed that the Arg residue in position 7, which is known to be crucial for Dyn A’s biological activity, is not necessary, and that a type I β-turn structure at the C-terminal part of both ligands plays an important role in retaining good binding affinities at the BRs. Our lead ligand 14 blocked Dyn A-(2-13) 10-induced hyperalgesiceffects and motor impairment in in vivo assays using naïve rats. In a model of peripheral neuropathy, intrathecal (i.th.) administration of ligand 14 reversed thermal hyperalgesia and mechanical hypersensitivity in a dose-dependent manner in nerve-injured rats. Thus, ligand 14 may inhibit abnormal pain states by blocking the neuroexcitatory effects of enhanced levels of dynorphin A, which are likely to be mediated by BRs in the spinal cord.

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