N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation via Nonhematopoietic TRPV1

Abstract

N-Arachidonoyl dopamine (NADA) is an endogenous lipid that potently activates the transient receptor potential vanilloid 1 (TRPV1), which mediates pain and thermosensation. NADA is also an agonist of cannabinoid receptors 1 and 2. We have reported that NADA reduces the activation of cultured human endothelial cells by LPS and TNF-α. Thus far, in vivo studies using NADA have focused on its neurologic and behavioral roles. In this article, we show that NADA potently decreases in vivo systemic inflammatory responses and levels of the coagulation intermediary plasminogen activator inhibitor 1 in three mouse models of inflammation: LPS, bacterial lipopeptide, and polymicrobial intra-abdominal sepsis. We also found that the administration of NADA increases survival in endotoxemic mice. Additionally, NADA reduces blood levels of the neuropeptide calcitonin gene-related peptide but increases the neuropeptide substance P in LPS-treated mice. We demonstrate that the anti-inflammatory effects of NADA are mediated by TRPV1 expressed by nonhematopoietic cells and provide data suggesting that neuronal TRPV1 may mediate NADA’s anti-inflammatory effects. These results indicate that NADA has novel TRPV1-dependent anti-inflammatory properties and suggest that the endovanilloid system might be targeted therapeutically in acute inflammation.

TRPV1 is crucial for thermal homeostasis in the mouse by heat loss behaviors under warm ambient temperature

“…NADA is structurally similar to capsaicin and is the most potent endogenous ligand for TRPV1 with the ability to induce cation influx via the activation of TRPV1 49 . NADA attenuates cytokine increases in the plasma of mice treated with toll-like receptor 4 agonist lipopolysaccharide and toll-like receptor 2 agonist Pam3Cys in a TRPV1-dependent manner 50 .…”

Anti-inflammatory dopamine- and serotonin-based endocannabinoid epoxides reciprocally regulate cannabinoid receptors and the TRPV1 channel

“…Primary sensory afferent neurons and immune cells are rich sources of lipid mediators that regulate pain due to inflammation. Previous studies have demonstrated the antiinflammatory actions of eVDs [98][99][100] ; thus, we hypothesize that epoxy-eVDs would also be antiinflammatory. Microglial cells play an important role in neuroinflammation and neuropathic pain.…”

“…Previous studies have shown that NADA mediates anti-inflammation via TRPV1 98 . Therefore, we next investigated the actions of eVDs and epoxy-eVDs at TRPV1 using HEK cells stably expressing human TRPV1.…”

The Endocannabinoid System May Modulate Sleep Disorders in Aging

“…Next, the quest of the endogenous ligands that naturally bind to these receptors leads to the discovery of the first agonist to the cannabinoid receptors named arachidonoylethanolamine or anandamide, and in later years, the second lipid with cannabimimetic properties was described: 2arachidonylglycerol (2-AG) [72]. Currently, the family of the endocannabinoids comprises different compounds aside anandamide and 2-AG, such as virodhamine, noladin ether, and N-arachidonyldopamine [73][74][75][76][77]. In addition, the endocannabinoid system is integrated by several molecular elements, including the enzymes that synthesize/degrade anandamide (fatty acid hydrolase [FAAH]) or 2-AG (monoacylglycerol lipase [MAGL]), the anandamide membrane transporter (AMT) and the receptor channel TRPV1 (Transient Receptor Potential Vanilloid 1; [78][79][80][81][82]).…”