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 1

Expression of opioid peptides in immune cells accumulating at the nerve injury site.

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Expression of opioid peptides in immune cells accumulating at the nerve ...
(A) Flow cytometric quantification of leukocytes (stained with CD45 Ab) and of CD45+ cells expressing opioids (stained with 3E7 Ab) at nerves and in hind paws. ipsi and contra, nerves ipsilateral and contralateral to surgeries, respectively; Nonoperated, nerves or paws from nonoperated animals. *P < 0.001, †P = 0.002; ‡P < 0.001, §P = 0.002, P = 0.039 versus nonoperated; #P = 0.021, **P < 0.001, ††P = 0.012, 2 days versus 14 days (t test). (B) Representative flow cytometric analysis of CD45+ cells (with CD45-phytoerythrin–cyanine dye 5 [Cy5] Ab) and of CD45+3E7+ cells (with 3E7-phytoerythrin Ab). Middle panels at 2 days and 14 days show control staining specificity of 3E7 Ab. (C) Representative double-immunofluorescence images showing coexpression of β-endorphin (END), Met-enkephalin (ENK), or dynorphin A (DYN) with CRF receptors (CRFR) in leukocytes (arrows) at injured nerves at 2 days and 14 days following CCI. Scale bars: 50 μm.