Immune cell–derived opioids protect against neuropathic pain in mice
Dominika Labuz, Yvonne Schmidt, Anja Schreiter, Heike L. Rittner, Shaaban A. Mousa, Halina Machelska
Dominika Labuz, Yvonne Schmidt, Anja Schreiter, Heike L. Rittner, Shaaban A. Mousa, Halina Machelska
View: Text | PDF | Corrigendum
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

×

Figure 5

Contribution of opioid receptors expressed in injured nerves to analgesia produced by CRF injected at the site of injury.

Options: View larger image (or click on image) Download as PowerPoint
Contribution of opioid receptors expressed in injured nerves to analgesi...
(A) Representative double-immunofluorescence images showing μ-, δ-, and κ-opioid receptor expression in sensory fibers (as determined by their coexpression with CGRP [arrows]) in the injured nerves at 2 and 14 days following CCI. Images are taken proximal to the most proximal ligature. Scale bars: 50 μm. (B) Left panels at 2 days and 14 days following CCI: Dose-dependent reversibility of CRF-induced (20 ng at 2 days or 100 ng at 14 days) analgesia by coinjection of antagonists selective to μ- (CTOP; 0.015–0.25 μg), δ- (ICI 174,864; 0.0625–2 μg), or κ-opioid (norBNI; 0.5–10 μg) receptors, as well as by an opioid receptor antagonist with limited access to the CNS, naloxone methiodide (NLXM; 0.625–5 μg) (P = 0.001 for CTOP at 2 days and P = 0.002 for CTOP at 14 days; P = 0.016 for ICI 174,864 at 2 days and P = 0.004 for ICI 174,864 at 14 days; P < 0.001 for norBNI and NLXM; ANOVA, linear regression). Right panels at 2 days and 14 days following CCI: Lack of reversibility of near-nerve CRF-induced (20 ng at 2 days or 100 ng at 14 days) analgesia s.c. at the neck injected with the most effective near-nerve doses of CTOP (0.25 μg), ICI 174,864 (2 μg), norBNI (10 μg), and NLXM (5 μg) (P > 0.05; ANOVA). The effects were measured in paws ipsilateral to CCI.