Abstract
Neuropathic pain typically appears in a region innervated by an injured or diseased nerve and, in some instances, also on the contralateral side. This so-called mirror image pain is often observed in mice lacking CB2 receptors after sciatic nerve injury, but the underlying mechanisms for this phenotype largely remain unclear. Here we focused on peripheral leptin signaling, which modulates neuropathic pain development and interacts with the endocannabinoid system. Leptin production is induced at the site of nerve injury in CB2-deficient mice (CB2-KO) mice and wild type controls (WT). However, induction of leptin receptor expression was only observed in the injured nerve of CB2-KO mice. This was paralleled by a stimulation of the leptin receptor-downstream STAT3 signaling and an infiltration of F4/80-positive macrophages. Interestingly, an upregulation of leptin receptor expression STAT3 activity and macrophage infiltration was also observed on the non-injured nerve of CB2-KO mice thus reflecting the mirror image pain in CB2-KO animals. Importantly, perineurally-administered leptin-neutralizing antibodies reduced mechanical hyperalgesia, blocked mirror image pain and inhibited the recruitment of F4/80-positive macrophages. These results identify peripheral leptin signaling as an important modulator of CB2 signaling in neuropathic pain.
Highlights
Neuropathic pain is elicited by an injury or inflammation of the nervous system
We show that leptin receptor expression and downstream signaling pathways are enhanced in cannabinoid receptor 2 (CB2) knockout mice after peripheral nerve injury and demonstrate that the peripheral blockade of leptin signaling with leptin-neutralizing antibodies completely blocked the development of contralateral hyperalgesia
To investigate the contribution of leptin activity on partial nerve ligation (PNL)-induced neuropathic pain, we first examined whether leptin or leptin receptor expression was modified by nerve injury
Summary
Neuropathic pain is elicited by an injury or inflammation of the nervous system. It typically appears in a region that is innervated by the affected nerve, but it can develop on the contralateral side. Most experimental animal models of neuropathic pain do not show symptoms of contralateral hyperalgesia, experimental protocols and genetic mouse lines in which mirror image pain can be induced have been described[1,2], such as mice with a genetic deletion of the cannabinoid CB2 receptor[3]. This receptor is mostly expressed on immune cells[4], whereas neurons prominently express cannabinoid CB1 receptors, CB2 is present on some neurons at very low levels[5,6]. We show that leptin receptor expression and downstream signaling pathways are enhanced in CB2 knockout mice after peripheral nerve injury and demonstrate that the peripheral blockade of leptin signaling with leptin-neutralizing antibodies completely blocked the development of contralateral hyperalgesia
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