leptin and Peripheral-Nerve-Injuries

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.

Topics: Animals; Antibodies, Neutralizing; Hyperalgesia; Leptin; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuralgia; Peripheral Nerve Injuries; Receptor, Cannabinoid, CB2; Receptors, Leptin; Sciatic Nerve; Signal Transduction; STAT3 Transcription Factor; Up-Regulation

The main aim of this study was to research new treatments following peripheral nerve injury involving melatonin (Mel), acetyl-l-carnitine (ALCAR), and leptin (Lep) using updated unbiased methods at the stereological and electron microscopic levels.. Wistar albino rats were randomly divided into nine equal groups; control (Cont), obese control (OG), obese group exposed to sciatic nerve resection (Gap) (OGG), obese group injected intraperitoneally (i.p.) with Mel (OMG), obese group injected with Mel i.p. with gap (OMGG), obese group injected with Lep i.p. (OLG), obese group injected with Lep i.p. with gap (OLGG), obese group injected with ALCAR i.p. (OAG), and obese group injected with ALCAR i.p. with gap (OAGG). Electromyography (EMG) procedures were performed. Following routine histological procedures, stereological analysis was performed for each group.. In terms of the number of myelinated axons, high significant increase in OGG was observed compared to OG and Cont (p < 0.01). In addition, a highly significant increase in axon surface area and myelin thickness of OGG compared to OG and Cont (p < 0.01) was noted. A significant decrease in myelin thickness/axon diameter ratio of OGG was found in comparison with the other groups. In terms of latency, there was a highly significant decrease in OGG compared to Cont and OG (p < 0.01). Myelinated axon numbers in OAGG, OMGG and OLGG increased highly significantly compared to other groups (p < 0.01). Latency in OMGG, a highly significant increase, was determined in OMG compared to Cont (p < 0.01). In addition, latency values in OGG were highly significantly greater than in OAC and OAGG (p < 0.01).. In particular, administration of Lep, Mel and ALCAR as neuroprotective agents may make a positive contribution to regeneration and myelination in obese rats.

Topics: Acetylcarnitine; Animals; Female; Leptin; Melatonin; Microscopy, Electron; Nerve Regeneration; Obesity; Peripheral Nerve Injuries; Random Allocation; Rats; Rats, Wistar

Leptin, an adipocytokine produced mainly by white adipose tissue, has a broad role in the regulation of neuronal functions. Accumulating evidence has revealed that leptin plays an important role in influencing neuropathic pain, shown recently by the finding that chronic administration of leptin induced thermal hyperalgesia and mechanical allodynia in naïve rats. Chronic constriction sciatic nerve injury (CCI) is a well characterized model used for studying neuropathic pain. The present study was designed to investigate whether leptin plays a role in neuropathic pain in rats induced by CCI by examining particular pain behaviors.. After sciatic nerve injury in rats, endogenous levels of leptin and leptin receptor (OB-Rb) were increased in a time dependent manner within the ipsilateral dorsal root ganglion (DRG). Intrathecal administration of leptin once daily for 6 days, beginning 7 days after CCI, alleviated neuropathic pain and decreased the expression of IL-6, TNFα, and the P2X2 and P2X3 receptors. Attenuation of endogenous OB-Rb in the DRG by intrathecal administration of OB-Rb antisense oligonucleotides did not change thermal hyperalgesia or mechanical allodynia induced by CCI.. Our findings suggest that exogenous leptin can alleviate the chronic neuropathic pain caused by CCI. The leptin effect may be mediated by attenuated expression of IL-6, TNFα, and the P2X2 and P2X3 receptors in the DRG of CCI rats.

Topics: Animals; Leptin; Male; Neuralgia; Peripheral Nerve Injuries; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2X2; Receptors, Purinergic P2X3; Sciatic Nerve