Abstract
Neuropathic pain is a debilitating chronic disease often resulting from damage to peripheral nerves. Activation of opioid receptors on peripheral sensory neurons can attenuate pain without central nervous system side effects. Here we aimed to analyze the distribution of neuronal μ-opioid receptors, the most relevant opioid receptors in the control of clinical pain, along the peripheral neuronal pathways in neuropathy. Hence, following a chronic constriction injury of the sciatic nerve in mice, we used immunohistochemistry to quantify the μ-receptor protein expression in the dorsal root ganglia (DRG), directly at the injured nerve trunk, and at its peripheral endings in the hind paw skin. We also thoroughly examined the μ-receptor antibody staining specificity. We found that the antibody specifically labeled μ-receptors in human embryonic kidney 293 cells as well as in neuronal processes of the sciatic nerve and hind paw skin dermis, but surprisingly not in the DRG, as judged by the use of μ/δ/κ-opioid receptor knockout mice. Therefore, a reliable quantitative analysis of μ-receptor expression in the DRG was not possible. However, we demonstrate that the μ-receptor immunoreactivity was strongly enhanced proximally to the injury at the nerve trunk, but was unaltered in paws, on days 2 and 14 following injury. Thus, μ-opioid receptors at the site of axonal damage might be a promising target for the control of painful neuropathies. Furthermore, our findings suggest a rigorous tissue-dependent characterization of antibodies' specificity, preferably using knockout animals.
Highlights
Neuropathic pain can result from peripheral nerve injuries such as amputation, entrapment, or compression
No positively stained cells were found in untransfected human embryonic kidney (HEK) 293 cells or HEK 293 cells transfected with the mouse d-opioid receptor fused with enhanced green fluorescent protein (eGFP), which appeared in green in the absence of the m-receptor antibody (Fig. 1)
M-Opioid receptor antibody staining in dorsal root ganglia (DRG) neurons Specific staining of the m-receptor antibody in HEK 293 cells prompted us to analyze the impact of nerve damage on m-receptor expression in peripheral sensory pathways
Summary
Neuropathic pain can result from peripheral nerve injuries such as amputation, entrapment, or compression. Such neuropathies trigger maladaptive alterations in the nervous system leading to peripheral and central sensitization that underlie transition to chronic pain [1]. Therapy with classical opioids predominantly acting at m-opioid receptors is limited by detrimental effects, including respiratory failure, nausea, dependence, and addiction mediated in the central nervous system [2]. These side effects can be avoided by activating opioid receptors on peripheral sensory neurons. Opioid peptides derived from immune cells accumulating at the site of nerve injury [13,14] or exogenous mreceptor agonists injected at this site [15] reversed mechanical or thermal hypersensitivity, suggesting that opioid receptors at the nerve injury site are functional
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