Pain A Painful Endogenous Opioid

Nancy R. Gough

Science's STKE, AAAS, Washington, DC 20005, USA

Dynorphin A_1-17 is derived from proteolytic processing of prodynorphin and has high affinity for µ, , and opioid receptors. However, increased amounts of dynorphin A are found in models of chronic pain, and antibodies against dynorphin A alleviate, rather than potentiate, pain. Lai et al. show that a fragment of dynorphin A that has low affinity for the opioid receptors (dynorphin A_2-13) stimulated a transient increase in intracellular calcium concentration in cultured embryonic dorsal root ganglion (DRG) cells and in F-11 cells, a neuroblastoma-DRG hybridoma. The increase in intracellular calcium was blocked by selective inhibition of L-type or P/Q-type voltage-sensitive calcium channels. A bradykinin B2 antagonist blocked the dynorphin-induced increase in intracellular calcium, and transfection of either the bradykinin B2 or B1 receptor reconstituted dynorphin A_2-13 responsiveness in cells that had spontaneously lost the ability to respond to dynorphin A. Dynorphin A_2-13 or dynorphin A_1-17 competed for binding to B1 or B2 receptors, suggesting that dynorphin is acting as an agonist at the bradykinin receptors. In rats, intrathecal injection of dynorphin A_2-13 caused enhanced sensitivity to touch and heat, and these effects were reversed by injection of a B2 receptor antagonist. Furthermore, knockout mice lacking B2 receptors did not show hypersensitive responses in response to dynorphin A_2-13 injection. Finally, in a rat model of neuropathic pain, B2 receptor and prodynorphin transcript abundance were increased in the DRG of rats as early as day 2 after nerve injury, and treatment with a B2 antagonist after nerve injury prevented hypersensitivity responses. As discussed by Altier and Zamponi, it appears that under conditions of chronic pain, enhanced production of dynorphin in the spinal cord produces a hyperalgesia response instead of an analgesic response through the ability of dynorphin to activate spinal bradykinin receptors.

J. Lai, M.-C. Luo, Q. Chen, S. Ma, L. R. Gardell, M. H. Ossipov, F. Porreca, Dynorphin A activates bradykinin receptors to maintain neuropathic pain. Nat. Neurosci. 9, 1534-1540 (2006). [PubMed]

C. Altier, G. W. Zamponi, Opioid, cheating on its receptors, exacerbates pain. Nat. Neurosci. 9, 1465-1467 (2006). [PubMed]

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