Immune cell–derived opioids protect against neuropathic pain in mice
Dominika Labuz, … , Shaaban A. Mousa, Halina Machelska
Dominika Labuz, … , Shaaban A. Mousa, Halina Machelska
Published January 12, 2009
Citation Information: J Clin Invest. 2009;119(2):278-286. https://doi.org/10.1172/JCI36246.
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Research Article Neuroscience

Immune cell–derived opioids protect against neuropathic pain in mice

Abstract

The analgesic effects of leukocyte-derived opioids have been exclusively demonstrated for somatic inflammatory pain, for example, the pain associated with surgery and arthritis. Neuropathic pain results from injury to nerves, is often resistant to current treatments, and can seriously impair a patient’s quality of life. Although it has been recognized that neuronal damage can involve inflammation, it is generally assumed that immune cells act predominately as generators of neuropathic pain. However, in this study we have demonstrated that leukocytes containing opioids are essential regulators of pain in a mouse model of neuropathy. About 30%–40% of immune cells that accumulated at injured nerves expressed opioid peptides such as β-endorphin, Met-enkephalin, and dynorphin A. Selective stimulation of these cells by local application of corticotropin-releasing factor led to opioid peptide–mediated activation of opioid receptors in damaged nerves. This ultimately abolished tactile allodynia, a highly debilitating heightened response to normally innocuous mechanical stimuli, which is symptomatic of neuropathy. Our findings suggest that selective targeting of opioid-containing immune cells promotes endogenous pain control and offers novel opportunities for management of painful neuropathies.

Authors

Dominika Labuz, Yvonne Schmidt, Anja Schreiter, Heike L. Rittner, Shaaban A. Mousa, Halina Machelska

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Figure 2

Analgesic effects produced by CRF injected at the site of nerve injury.

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Analgesic effects produced by CRF injected at the site of nerve injury. ...
(A) Dose-response relationships of CRF-induced analgesia measured 30 minutes after CRF application, in paws ipsilateral to CCI at 2 days (5–20 ng) and at 14 days (20–100 ng) following CCI (P < 0.001 and P = 0.003, respectively; ANOVA, linear regression). No significant changes were observed in paws contralateral to CCI (P > 0.05, ANOVA). (B) The time course of CRF-induced analgesia in paws ipsilateral to CCI at 2 days (20 ng) and at 14 days (100 ng) following CCI (*P < 0.05 compared with 0 time point; repeated-measures ANOVA, Dunnett’s test). There were no significant changes in control groups (P > 0.05 compared with 0 time point; repeated-measures ANOVA). (C) Dose-dependent reversibility of CRF-induced (20 ng at 2 days or 100 ng at 14 days) analgesia by coinjection of CRF receptor antagonist α-helical CRF (0.125–2 ng), in paws ipsilateral to CCI at 2 days and 14 days (P < 0.001; ANOVA, linear regression). (D) Dose-dependent reversibility of CRF-induced (20 ng at 2 days or 100 ng at 14 days) analgesia by coinjection of Abs against β-endorphin (Anti-END; 0.015–0.25 μg), Met-enkephalin (Anti-ENK; 0.0625–0.5 μg), or dynorphin A (Anti-DYN; 0.5–4 μg), in paws ipsilateral to CCI at 2 days and 14 days after nerve injury (P < 0.001; ANOVA, linear regression).