Pinning down neuropathic pain

Neuropathic pain, a widespread chronic condition caused by injury to the nervous system, is one of the most difficult syndromes to treat successfully with drugs. New therapeutic approaches to the treatment of this condition require a better understanding of the molecular mechanisms that underlie its development. Lai and colleagues, reporting in Nature Neuroscience, have now uncovered an important piece of the puzzle. The discovery that dynorphin A, an opioid neuropeptide, promotes chronic pain through its agonist action at bradykinin receptors, could pave the way for new treatment options.

Many experimental models of chronic pain show significant and time-dependent regional elevation of dynorphin A, where it is known to mediate inhibitory effects on pain regulation by binding to opioid receptors. Dynorphin A also mediates excitatory effects by an unknown mechanism. Now further receptors for dynorphin A have been discovered. A des-tyrosyl fragment of dynorphin A (dynorphin A2–13) with very low affinity for opioid receptors, was shown to induce Ca2+ influx by binding to B1 and B2 bradykinin receptors in vitro in embryonic dorsal root ganglia (DRG) and in a model cell line for peripheral sensory neurons. This led to the activation of L-type and P/Q type voltage-sensitive calcium channels, possibly by inducing bradykinin receptor coupling to the Gs–cAMP–PKA pathway.

Importantly, in vivo experiments demonstrated that administration of dynorphin A2–13 into the spinal canal of rats induced reversible hypersensitivity and hyperalgesia, an effect that was not observed in bradykinin-receptor-B2-knockout mice. In a model of neuropathic pain induced by spinal nerve ligation (SNL), the bradykinin B2 antagonist HOE 140 led to a reversal of the chronic pain state. SNL induced time-dependent upregulation of dynorphin, which has a delayed onset and reached its peak 7–10 days after injury. The reversal with HOE 140 was similarly time-dependent, with no effect at 2 days after SNL, but a complete block of injury-induced pain 7 days post-SNL. Combined with the analysis of prodynorphin-A-knockout mice, and bradykinin and dynorphin A expression patterns, B2 receptor activation by dynorphin was demonstrated to be necessary for the maintenance, but not onset, of neuropathic pain.

This identifies dynorphin as a neuropeptide that can activate two classes of receptors with diverse structure and function — the opioid and bradykinin receptors — and induces a signalling pathway at bradykinin receptors that is distinct from activation with bradykinin itself. Bradykinin receptor antagonists have been investigated for many years. As selective inhibition of dynorphin A at the bradykinin receptors relieved chronic pain without interfering with essential peripheral functions of bradykinin or dynorphin A at opioid receptors, there is new hope for the treatment of debilitating neuropathic pain.


  1. 1

    Lai, J. et al. Dynorphin A activates bradykinin receptors to maintain neuropathic pain. Nature Neurosci. 9, 1534–1540 (2006)

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Flemming, A. Pinning down neuropathic pain. Nat Rev Drug Discov 6, 24–25 (2007).

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