leptin and Neuralgia

Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity.

Topics: Adrenomedullin; Animals; Calcitonin Gene-Related Peptide; Ghrelin; Humans; Inflammation; Inflammation Mediators; Leptin; Macrophage Activation; Microglia; Neuralgia; Neurodegenerative Diseases; Neuroglia; Neuropeptide Y; Neuropeptides; Pain; Pro-Opiomelanocortin; Tachykinins; Vasoactive Intestinal Peptide

The endocannabinoid system is under active investigation as a pharmacological target for obesity management due to its role in appetite regulation and metabolism. Exogenous cannabinoids such as tetrahydrocannabinol (THC) stimulate appetite and food intake. However, there are no controlled observations directly linking THC to changes of most of the appetite hormones.. We took the opportunity afforded by a placebo-controlled trial of smoked medicinal cannabis for HIV-associated neuropathic pain to evaluate the effects of THC on the appetite hormones ghrelin, leptin and PYY, as well as on insulin.. In this double-blind cross-over study, each subject was exposed to both active cannabis (THC) and placebo.. Compared to placebo, cannabis administration was associated with significant increases in plasma levels of ghrelin and leptin, and decreases in PYY, but did not significantly influence insulin levels.. These findings are consistent with modulation of appetite hormones mediated through endogenous cannabinoid receptors, independent of glucose metabolism.

Topics: Adult; Analgesics, Non-Narcotic; Appetite; Double-Blind Method; Dronabinol; Ghrelin; HIV Infections; Hormones; Humans; Leptin; Male; Middle Aged; Neuralgia; Peptide YY; Pilot Projects

Leptin is an adipocytokine that is primarily secreted by white adipose tissue, and it contributes to the pathogenesis of neuropathic pain in collaboration with N-methyl-D-aspartate receptors (NMDARs). Functional NMDARs are a heteromeric complex that primarily comprise two NR1 subunits and two NR2 subunits. NR2A is preferentially located at synaptic sites, and NR2B is enriched at extrasynaptic sites. The roles of synaptic and extrasynaptic NMDARs in the contribution of leptin to neuropathic pain are not clear. The present study examined whether the important role of leptin in neuropathic pain was related to synaptic or extrasynaptic NMDARs. We used a rat model of spared nerve injury (SNI) and demonstrated that the intrathecal administration of the NR2A-selective antagonist NVP-AAM077 and the NR2B-selective antagonist Ro25-6981 prevented and reversed mechanical allodynia following SNI. Administration of exogenous leptin mimicked SNI-induced behavioral allodynia, which was also prevented by NVP-AAM077 and Ro25-6981. Mechanistic studies showed that leptin enhanced NR2B- but not NR2A-mediated currents in spinal lamina II neurons of naïve rats. Leptin also upregulated the expression of NR2B, which was blocked by the NR2B-selective antagonist Ro25-6981, in cultured dorsal root ganglion (DRG) neurons. Leptin enhanced neuronal nitric oxide synthase (nNOS) expression, which was also blocked by Ro25-6981, in cultured DRG cells. However, leptin did not change NR2A expression, and the NR2A-selective antagonist NVP-AAM077 had no effect on leptin-enhanced nNOS expression. Our data suggest an important cellular link between the spinal effects of leptin and the extrasynaptic NMDAR-nNOS-mediated cellular mechanism of neuropathic pain.

Topics: Animals; Behavior, Animal; Cells, Cultured; Ganglia, Spinal; Hyperalgesia; Leptin; Male; Nerve Tissue; Neuralgia; Neurons; Nitric Oxide Synthase Type I; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Synapses

Accumulating evidence demonstrates the beneficial effects of physical exercise on pain conditions; however, the underlying mechanisms are not understood thoroughly. The purpose of the present study was to investigate the effects of regular swimming exercise on neuroma pain and the possible roles of adipokines (leptin and adiponectin) in the pain behaviors modulated by exercise. The results showed that 5 weeks of regular swimming exercise relieved pain behaviors in a rat model of neuroma pain and normalized the dysregulation of circulating leptin and adiponectin in plasma induced by nerve injury. Moreover, regular swimming exercise reversed the altered expressions of leptin receptor and adiponectin receptor 1 in neuroma. In addition, the administration of exogenous leptin to the neuroma site dampened the effects of regular swimming exercise on neuroma pain and adiponectin administration alleviated the neuroma pain in the non-exercised neuroma rats. These findings indicate that leptin and adiponectin might be involved in mediating the beneficial effects of exercise on neuroma pain. PERSPECTIVE: Perspective: Identifying which endogenous processes are activated by specific exercise regimes would likely reveal novel therapeutic targets for the treatment of neuropathic pain. The current study suggests that adipokines might be involved in pain behaviors modulated by exercise and thus presents them as potential targets for pain management.

Topics: Adiponectin; Animals; Disease Models, Animal; Exercise Therapy; Leptin; Male; Neuralgia; Neuroma; Pain Management; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Swimming

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

Preganglionic cervical root avulsion (PCRA) affects both the peripheral and central nervous systems and is often associated with neuropathic pain. Unlike peripheral nerve injuries (PNI), central lesions caused by disruption of cervical roots from the spinal cord following PCRA contribute to the generation of neuropathic pain. Leptin is involved in the development of neuropathic pain after PNI by affecting neurons. However, whether leptin is involved in microglial activation leading to neuropathic pain after PCRA is unknown.. Leptin is essential for the development of neuropathic pain after PCRA. Allodynia was absent in the leptin-deficient mice and the mice administered the leptin antagonist. We also found that leptin deficiency or the administration of its antagonist inhibited the development of microgliosis in the dorsal horn and brainstem. Furthermore, increase in the expression of CD86 and iNOS, and Wallerian degeneration were noted in the spinal cord. The administration of exogenous leptin to leptin-deficient mice reversed these effects.. We concluded that leptin is involved in the proliferation and activation of microglia, which in turn enhances the development of neuropathic pain. Blocking the effects of leptin might be a target for the treatment of neuropathic pain after PCRA.

Topics: Animals; B7-2 Antigen; Brain Stem; Cell Proliferation; Cervical Cord; Female; Fractures, Avulsion; Gliosis; Leptin; Male; Mice; Mice, Transgenic; Microglia; Neuralgia; Nitric Oxide Synthase Type II; Pain Measurement; Spinal Cord; Spinal Cord Dorsal Horn; Wallerian Degeneration

Leptin is widely distributed in many tissues, including the nervous system. However, the ontogeny of leptin expression in the dorsal root ganglion (DRG) is unclear. Recent studies have shown that leptin is involved in the regulation of neuropathic pain induced by nerve injury. Our previous results showed that exogenous leptin administration alleviated the pain behaviors induced by chronic constriction sciatic nerve injury. In the present study, the ontogenic expression of leptin was detected in the DRG of the mouse embryo at days 15.5 (E15.5), E17.5, and E19.5 of gestation and in the postnatal mouse at days 5 (P5), P15, and P25, and in the adult mouse. Leptin immunoreactivity and mRNA were not found in DRG at E15.5. The percentage of leptin immunopositive (leptin) neurons was about 27% at E17.5. It continued to increase to about 70% at P5. From P5 to P15, there was no significant change. The proportion of DRG neurons positive for leptin decreased after P15 and there were about 41% leptin neurons in adults. The expression profile of leptin mRNA is similar to leptin immunoreactivity. Oxaliplatin (OXA) is an effective platinum-based drug used as first-line chemotherapy for advanced colorectal cancer. However, it may induce neuropathic pain. In the current study, we found that the expression of leptin was increased in the lumbar 4-6 DRG of OXA-treated mice. These results indicate that leptin is involved in the regulation of DRG development and OXA-induced neuropathic pain.

Topics: Animals; Animals, Newborn; Cold Temperature; Disease Models, Animal; Ganglia, Spinal; Hyperalgesia; Leptin; Lumbar Vertebrae; Male; Mice, Inbred C57BL; Neuralgia; Neurons; Organoplatinum Compounds; Oxaliplatin; Random Allocation; RNA, Messenger; Touch

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

Spinal cord injury is a major cause of long-term disability and has no current clinically accepted treatment. Leptin, an adipocyte-derived hormone, is best known as a regulator of food intake and energy expenditure. Interestingly, several studies have demonstrated that leptin has significant effects on proliferation and cell survival in different neuropathologies. Here, we sought to evaluate the role of leptin after spinal cord injury.. Based on its proposed neuroprotective role, we have evaluated the effects of a single, acute intraparenchymal injection of leptin in a clinically relevant animal model of spinal cord injury. As determined by quantitative Real Time-PCR, endogenous leptin and the long isoform of the leptin receptor genes show time-dependent variations in their expression in the healthy and injured adult spinal cord. Immunohistochemical analysis of post-injury tissue showed the long isoform of the leptin receptor expression in oligodendrocytes and, to a lesser extent, in astrocytes, microglia/macrophages and neurons. Moreover, leptin administered after spinal cord injury increased the expression of neuroprotective genes, reduced caspase-3 activity and decreased the expression of pro-inflammatory molecules. In addition, histological analysis performed at the completion of the study showed that leptin treatment reduced microglial reactivity and increased caudal myelin preservation, but it did not modulate astroglial reactivity. Consequently, leptin improved the recovery of sensory and locomotor functioning.. Our data suggest that leptin has a prominent neuroprotective and anti-inflammatory role in spinal cord damage and highlights leptin as a promising therapeutic agent.

Topics: Animals; Anti-Inflammatory Agents; Astrocytes; Gene Expression Profiling; Inflammation; Leptin; Locomotion; Macrophages; Male; Microglia; Neuralgia; Neurons; Neuroprotective Agents; Oligodendroglia; Peroxisome Proliferator-Activated Receptors; Rats; Rats, Wistar; Receptors, Leptin; Spinal Cord; Spinal Cord Injuries; Transcription, Genetic; Treatment Outcome; Up-Regulation

Recent studies have shown that leptin (an adipocytokine) played an important role in nociceptive behavior induced by nerve injury, but the cellular mechanism of this action remains unclear. Using the whole-cell patch-clamp recording from rat's spinal cord slices, we showed that superfusion of leptin onto spinal cord slices dose-dependently enhanced N-methyl-d-aspartate (NMDA) receptor-mediated currents in spinal cord lamina II neurons. At the cellular level, the effect of leptin on spinal NMDA-induced currents was mediated through the leptin receptor and the JAK2/STAT3 (but not PI3K or MAPK) pathway, as the leptin effect was abolished in leptin receptor-deficient (db/db) mice and inhibited by a JAK/STAT inhibitor. Moreover, we demonstrated in naïve rats that a single intrathecal administration of leptin enhanced spontaneous biting, scratching, and licking behavior induced by intrathecal NMDA and that repeated intrathecal administration of leptin elicited thermal hyperalgesia and mechanical allodynia, which was attenuated by the noncompetitive NMDA receptor antagonist MK-801. Intrathecal leptin also upregulated the expression of NMDA receptors and pSTAT3 within the rat's spinal cord dorsal horn, and intrathecal MK-801 attenuated this leptin effect as well. Our data demonstrate a relationship between leptin and NMDA receptor-mediated spinal neuronal excitation and its functional role in nociceptive behavior. Since leptin contributes to nociceptive behavior induced by nerve injury, the present findings suggest an important cellular link between the leptin's spinal effect and the NMDA receptor-mediated cellular mechanism of neuropathic pain. A functional link is demonstrated between leptin, an adipocytokine, and the cellular mechanisms of neuropathic pain via enhancement of function and expression of spinal N-methyl-d-aspartate receptors.

Topics: Analysis of Variance; Animals; Behavior, Animal; Dizocilpine Maleate; Drug Interactions; Electric Stimulation; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Hyperalgesia; In Vitro Techniques; Leptin; Male; Membrane Potentials; Mice; Mice, Knockout; N-Methylaspartate; Neuralgia; Pain Measurement; Patch-Clamp Techniques; Physical Stimulation; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Receptors, N-Methyl-D-Aspartate; Sensory Receptor Cells; Signal Transduction; Spinal Cord; STAT3 Transcription Factor; Up-Regulation