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Obesity increases nociceptive activation of the trigeminal system.

ABSTRACT: BACKGROUND:Obesity is a risk factor associated with several pain syndromes. However, the mechanisms underlying the association between obesity and pain are not known. The aim of this study was to test the hypothesis that obesity enhances neuronal responses to nociceptive stimulation within the trigeminal nucleus caudalis (TNC). METHODS:Male and female C57BL/6J mice were fed a high-fat or regular diet from the time of weaning until 20 weeks of age. We then quantified neuronal activation by measuring Fos immunoreactivity within the TNC in response to a facial injection of a low dose of capsaicin (1 ?g/10 ?L). RESULTS:We found that 0.01% capsaicin did not significantly increase Fos immunoreactivity in control mice fed a regular diet. In contrast, this low dose of capsaicin caused a 3.3-fold increase in Fos in the TNC in obese mice (p < 0.001). CONCLUSIONS:These results support the hypothesis that diet-induced obesity in mice enhances nociceptive processing within the TNC. Diet-induced obesity may be a useful model for mechanistic studies. Future studies will improve our understanding of how obesity may contribute to trigeminal pain by sensitizing the trigeminal nociceptive system.

SUBMITTER: Rossi HL

PROVIDER: S-EPMC4275045 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Obesity increases nociceptive activation of the trigeminal system.

Rossi H L HL Luu A K S AK DeVilbiss J L JL Recober A A

European journal of pain (London, England) 20121016 5

<h4>Background</h4>Obesity is a risk factor associated with several pain syndromes. However, the mechanisms underlying the association between obesity and pain are not known. The aim of this study was to test the hypothesis that obesity enhances neuronal responses to nociceptive stimulation within the trigeminal nucleus caudalis (TNC).<h4>Methods</h4>Male and female C57BL/6J mice were fed a high-fat or regular diet from the time of weaning until 20 weeks of age. We then quantified neuronal activ ...[more]

PMID: 23070979

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Project description:BACKGROUND:Obesity is a worldwide epidemic, and severe obesity is a risk factor for many diseases, including diabetes, heart disease, stroke, and some cancers. Endocannabinoid system (ECS) signaling in the brain and peripheral tissues is activated in obesity and plays a role in the regulation of body weight. The main research question here was whether quantitative measurement of plasma endocannabinoids, anandamide, and related N-acylethanolamines (NAEs), combined with genotyping for mutations in fatty acid amide hydrolase (FAAH) would identify circulating biomarkers of ECS activation in severe obesity. METHODOLOGY/PRINCIPAL FINDINGS:Plasma samples were obtained from 96 severely obese subjects with body mass index (BMI) of > or = 40 kg/m(2), and 48 normal weight subjects with BMI of < or = 26 kg/m(2). Triple-quadrupole mass spectroscopy methods were used to measure plasma ECS analogs. Subjects were genotyped for human FAAH gene mutations. The principal analysis focused on the FAAH 385 C-->A (P129T) mutation by comparing plasma ECS metabolite levels in the FAAH 385 minor A allele carriers versus wild-type C/C carriers in both groups. The main finding was significantly elevated mean plasma levels of anandamide (15.1+/-1.4 pmol/ml) and related NAEs in study subjects that carried the FAAH 385 A mutant alleles versus normal subjects (13.3+/-1.0 pmol/ml) with wild-type FAAH genotype (p = 0.04), and significance was maintained after controlling for BMI. CONCLUSIONS/SIGNIFICANCE:Significantly increased levels of the endocannabinoid anandamide and related NAEs were found in carriers of the FAAH 385 A mutant alleles compared with wild-type FAAH controls. This evidence supports endocannabinoid system activation due to the effect of FAAH 385 mutant A genotype on plasma AEA and related NAE analogs. This is the first study to document that FAAH 385 A mutant alleles have a direct effect on elevated plasma levels of anandamide and related NAEs in humans. These biomarkers may indicate risk for severe obesity and may suggest novel ECS obesity treatment strategies.

Project description:OBJECTIVE:The goal of this narrative review is to provide an overview of migraine pathophysiology, with an emphasis on the role of calcitonin gene-related peptide (CGRP) within the context of the trigeminovascular system. BACKGROUND:Migraine is a prevalent and disabling neurological disease that is characterized in part by intense, throbbing, and unilateral headaches. Despite recent advances in understanding its pathophysiology, migraine still represents an unmet medical need, as it is often underrecognized and undertreated. Although CGRP has been known to play a pivotal role in migraine for the last 2 decades, this has now received more interest spurred by the early clinical successes of drugs that block CGRP signaling in the trigeminovascular system. DESIGN:This narrative review presents an update on the role of CGRP within the trigeminovascular system. PubMed searches were used to find recent (ie, 2016 to November 2018) published articles presenting new study results. Review articles are also included not as primary references but to bring these to the attention of the reader. Original research is referenced in describing the core of the narrative, and review articles are used to support ancillary points. RESULTS:The trigeminal ganglion neurons provide the connection between the periphery, stemming from the interface between the primary afferent fibers of the trigeminal ganglion and the meningeal vasculature and the central terminals in the trigeminal nucleus caudalis. The neuropeptide CGRP is abundant in trigeminal ganglion neurons, and is released from the peripheral nerve and central nerve terminals as well as being secreted within the trigeminal ganglion. Release of CGRP from the peripheral terminals initiates a cascade of events that include increased synthesis of nitric oxide and sensitization of the trigeminal nerves. Secreted CGRP in the trigeminal ganglion interacts with adjacent neurons and satellite glial cells to perpetuate peripheral sensitization, and can drive central sensitization of the second-order neurons. A shift in central sensitization from activity-dependent to activity-independent central sensitization may indicate a mechanism driving the progression of episodic migraine to chronic migraine. The pathophysiology of cluster headache is much more obscure than that of migraine, but emerging evidence suggests that it may also involve hypersensitivity of the trigeminovascular system. Ongoing clinical studies with therapies targeted at CGRP will provide additional, valuable insights into the pathophysiology of this disorder. CONCLUSIONS:CGRP plays an essential role in the pathophysiology of migraine. Treatments that interfere with the functioning of CGRP in the peripheral trigeminal system are effective against migraine. Blocking sensitization of the trigeminal nerve by attenuating CGRP activity in the periphery may be sufficient to block a migraine attack. Additionally, the potential exists that this therapeutic strategy may also alleviate cluster headache as well.

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Obesity increases nociceptive activation of the trigeminal system.

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Obesity increases nociceptive activation of the trigeminal system.

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