ABSTRACT
BACKGROUND: Energy metabolism disorders and neurogenic inflammation play important roles in the central sensitization to chronic migraine (CM). AMP-activated protein kinase (AMPK) is an intracellular energy sensor, and its activation regulates inflammation and reduces neuropathic pain. However, studies on the involvement of AMPK in the regulation of CM are currently lacking. Therefore, this study aimed to explore the mechanism underlying the involvement of AMPK in the central sensitization to CM. METHODS: Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC). Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured. The expression of calcitonin gene-related peptide (CGRP) and cytokines, M1/M2 microglia, and NF-κB pathway activation were detected after the intervention. RESULTS: Repeated NTG injections resulted in a gradual decrease in AMPK protein expression, and the negative regulation of AMPK by increased ubiquitin-like plant homeodomain and RING finger domain 1 (UHRF1) expression may counteract AMPK activation by increasing ADP/ATP. AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1ß, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10. Moreover, AMPK in TNC was mainly located in microglia. AICAR could reduce the expression of inducible NO synthase (iNOS) in M1 microglia and increase the expression of Arginase 1 (Arg1) in M2 microglia by inhibiting the activation of NF-κB pathway. CONCLUSIONS: AMPK was involved in the central sensitization of CM, and the activation of AMPK reduced neuroinflammation in NTG-induced CM mice. AMPK may provide new insights into interventions for energy metabolism disorders and neurogenic inflammation in migraine.
Subject(s)
Migraine Disorders , Nitroglycerin , Mice , Animals , Nitroglycerin/adverse effects , Microglia/metabolism , AMP-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Calcitonin Gene-Related Peptide/metabolism , Central Nervous System Sensitization/physiology , Neurogenic Inflammation/metabolism , Pain/metabolism , Migraine Disorders/chemically induced , Migraine Disorders/drug therapy , Migraine Disorders/metabolismABSTRACT
Psoriasis is an immune-mediated skin disease associated with neurogenic inflammation, but the underlying molecular mechanism remains unclear. We demonstrate here that acid-sensing ion channel 3 (ASIC3) exacerbates psoriatic inflammation through a sensory neurogenic pathway. Global or nociceptor-specific Asic3 knockout (KO) in female mice alleviates imiquimod-induced psoriatic acanthosis and type 17 inflammation to the same extent as nociceptor ablation. However, ASIC3 is dispensable for IL-23-induced psoriatic inflammation that bypasses the need for nociceptors. Mechanistically, ASIC3 activation induces the activity-dependent release of calcitonin gene-related peptide (CGRP) from sensory neurons to promote neurogenic inflammation. Botulinum neurotoxin A and CGRP antagonists prevent sensory neuron-mediated exacerbation of psoriatic inflammation to similar extents as Asic3 KO. In contrast, replenishing CGRP in the skin of Asic3 KO mice restores the inflammatory response. These findings establish sensory ASIC3 as a critical constituent in psoriatic inflammation, and a promising target for neurogenic inflammation management.
Subject(s)
Acid Sensing Ion Channels , Calcitonin Gene-Related Peptide , Mice, Knockout , Psoriasis , Sensory Receptor Cells , Animals , Acid Sensing Ion Channels/metabolism , Acid Sensing Ion Channels/genetics , Female , Psoriasis/metabolism , Psoriasis/pathology , Psoriasis/genetics , Psoriasis/chemically induced , Mice , Calcitonin Gene-Related Peptide/metabolism , Calcitonin Gene-Related Peptide/genetics , Sensory Receptor Cells/metabolism , Skin/metabolism , Skin/pathology , Imiquimod , Mice, Inbred C57BL , Disease Models, Animal , Inflammation/metabolism , Neurogenic Inflammation/metabolism , Humans , Nociceptors/metabolism , Interleukin-23/metabolism , Interleukin-23/geneticsABSTRACT
PURPOSE: To investigate the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) after subcutaneous injection of dexamethasone prior to skin incision in rats.METHODS:Twenty seven Wistar-EPM-1 rats were randomly divided into three groups. The sham group (SG) of rats was injected with 0.9 % saline. The second group (Dexa) was injected with 1.0 mg/kg dexamethasone, and the third group (Dexa+) was injected with 10.0 mg/kg dexamethasone. In all groups, the three subcutaneous injections were performed 30 minutes prior to the surgical skin incision and tissue collection. SP and CGRP (15 kDa pro-CGRP and 5 kDa CGRP) were quantified by Western Blotting.RESULTS: No statistically significant differences (p>0.05) were found in pro-CGRP, CGRP and SP values in all three groups.CONCLUSION:The anti-inflammatory effect of dexamethasone did not occur when the substance P and calcitonin gene-related peptide levels were altered during the neurogenic inflammation process of skin wound healing in rats.