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Dynorphin A activates bradykinin receptors to maintain neuropathic pain

Nature Neuroscience volume 9, pages 1534–1540 (2006)Cite this article

Abstract

Dynorphin A is an endogenous opioid peptide that produces non-opioid receptor-mediated neural excitation. Here we demonstrate that dynorphin induces calcium influx via voltage-sensitive calcium channels in sensory neurons by activating bradykinin receptors. This action of dynorphin at bradykinin receptors is distinct from the primary signaling pathway activated by bradykinin and underlies the hyperalgesia produced by pharmacological administration of dynorphin by the spinal route in rats and mice. Blockade of spinal B1 or B2 receptor also reverses persistent neuropathic pain but only when there is sustained elevation of endogenous spinal dynorphin, which is required for maintenance of neuropathic pain. These data reveal a mechanism for endogenous dynorphin to promote pain through its agonist action at bradykinin receptors and suggest new avenues for therapeutic intervention.

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Figure 1: Dynorphin A2–13 (dynA2–13) induces calcium influx in DRG and F-11 cells.
Figure 2: Inhibitory effect of VSCC blockers on dynorphin A2–13-induced [Ca2+]i in F-11 cells.
Figure 3: Inhibitory effect of B2 receptor–selective antagonist HOE 140 on dynorphin A2–13-induced [Ca2+]i in F-11 cells that express predominantly B2 receptors.
Figure 4: Heterologous expression of human B1 or human B2 receptors in F-11 cells that have spontaneously lost responsiveness to dynorphin A.
Figure 5: Effects of HOE 140 and DALBK on tactile hypersensitivity and thermal hyperalgesia induced by dynorphin A2–13.
Figure 6: Effects of intrathecal bradykinin receptor antagonists on the tactile and thermal hypersensitivities induced by L5–L6 SNL (n = 6–7).
Figure 7: Quantitative PCR analysis of bradykinin receptor, kininogen and prodynorphin transcripts in the DRG and spinal cord of sham control and L5–L6 SNL rats (n = 6).

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Acknowledgements

This work was supported by a grant from the National Institute on Drug Abuse. The authors appreciate the technical assistance of Y. Kawamoto on DRG cultures and H. Badghisi on the PI hydrolysis assay.

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Authors and Affiliations

  1. Department of Pharmacology, University of Arizona Health Sciences Center, 1501 N. Campbell Ave., Tucson, 85724, Arizona, USA

    Josephine Lai, Miaw-Chyi Luo, Qingmin Chen, Shouwu Ma, Luis R Gardell, Michael H Ossipov & Frank Porreca

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Contributions

M.-C.L. conducted the ratiometric imaging, designed and executed the PCR analyses, performed the data analysis and prepared the figures. Q.C. conducted the surgeries and behavioral experiments and data analysis.

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Correspondence to Josephine Lai.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

F-11 cells exhibit characteristics of nociceptive C-fibers. (PDF 2126 kb)

Supplementary Fig. 2

Voltage-sensitive calcium channels (VSCCs) are expressed in F-11 cells. (PDF 5352 kb)

Supplementary Fig. 3

Dynorphin A(2-13) has very low affinity for the cloned opioid receptors. (PDF 2764 kb)

Supplementary Fig. 4

Heterologous expression of the human bradykinin B1 or B2 receptor in F-11 cells. (PDF 4479 kb)

Supplementary Fig. 5

HOE 140 blocks dynorphin A(2-13)-induced [Ca2+]i in transfected F-11 expressing the human B2 receptor. (PDF 2362 kb)

Supplementary Methods (PDF 21 kb)

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Lai, J., Luo, MC., Chen, Q. et al. Dynorphin A activates bradykinin receptors to maintain neuropathic pain. Nat Neurosci 9, 1534–1540 (2006). https://doi.org/10.1038/nn1804

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