administration-9-tetrahydrocannabinol-thc-adolescent-adult

Administration of &#916;<sup>9</sup>-Tetrahydrocannabinol (THC) in Adolescent and Adult Mice

&#916;9-tetrahydrocannabinol (THC) is responsible for the intoxicating (psychotropic) effects of cannabis and cannabis-derived products currently ...

University of California, Irvine

Previous work suggests the existence of a paracrine signaling mechanism in which histamine released from visceral mast cells into the portal circulation contributes to fasting-induced ketogenesis by stimulating biosynthesis of the endogenous high-affinity PPAR-α agonist oleoylethanolamide (OEA).

Diet-Induced Obesity Disrupts Histamine-Dependent Oleoylethanolamide Signaling in the Mouse Liver.

During adolescence, microglia are actively involved in neocortical maturation while concomitantly undergoing profound phenotypic changes. Because the teenage years are also a time of experimentation with cannabis, we evaluated whether adolescent exposure to the drug's psychotropic constituent, Δ-tetrahydrocannabinol (THC), might persistently alter microglia function.

Frequent Low-Dose Δ-Tetrahydrocannabinol in Adolescence Disrupts Microglia Homeostasis and Disables Responses to Microbial Infection and Social Stress in Young Adulthood.

Cannabis use by adolescents is widespread, but its effects on the ovaries remain largely unknown. Δ9-tetrahydrocannabinol (THC) exerts its pharmacological effects by activating, and in some conditions hijacking, cannabinoid receptors (CBRs). We hypothesized that adolescent exposure to THC affects ovarian function in adulthood. Peripubertal female C57BL/6N mice were given THC (5 mg/kg) or its vehicle, once daily by intraperitoneal injection. Some mice received THC from postnatal day (PND) 30-33 and their ovaries were harvested PND34; other mice received THC from PND30-43, and their ovaries were harvested PND70. Adolescent treatment with THC depleted ovarian primordial follicle numbers by 50% at PND70, 4 weeks after the last dose. The treatment produced primordial follicle activation, which persisted until PND70. THC administration also caused DNA damage in primary follicles and increased PUMA protein expression in oocytes of primordial and primary follicles. Both CB1R and CB2R were expressed in oocytes and theca cells of ovarian follicles. Enzymes involved in the formation (N-acylphosphatidylethanolamine phospholipase D) or deactivation (fatty acid amide hydrolase) of the endocannabinoid anandamide were expressed in granulosa cells of ovarian follicles and interstitial cells. Levels of mRNA for CBR1 were significantly increased in ovaries after adolescent THC exposure, and upregulation persisted for at least 4 weeks. Our results support that adolescent exposure to THC may cause aberrant activation of the ovarian endocannabinoid system in female mice, resulting in substantial loss of ovarian reserve in adulthood. Relevance of these findings to women who frequently used cannabis during adolescence warrants investigation.

Adolescent exposure to low-dose Δ9-tetrahydrocannabinol depletes the ovarian reserve in female mice.

Circulating monocytes participate in pain chronification but the molecular events that cause their deployment are unclear. Using a mouse model of hyperalgesic priming (HP), we show that monocytes enable progression to pain chronicity through a mechanism that requires transient activation of the hydrolase, N-acylethanolamine acid amidase (NAAA), and the consequent suppression of NAAA-regulated lipid signaling at peroxisome proliferator-activated receptor-α (PPAR-α). Inhibiting NAAA in the 72 hours following administration of a priming stimulus prevented HP. This effect was phenocopied by NAAA deletion and depended on PPAR-α recruitment. Mice lacking NAAA in CD11b cells - monocytes, macrophages, and neutrophils - were resistant to HP induction. Conversely, mice overexpressing NAAA or lacking PPAR-α in the same cells were constitutively primed. Depletion of monocytes, but not resident macrophages, generated mice that were refractory to HP. The results identify NAAA-regulated signaling in monocytes as a control node in the induction of HP and, potentially, the transition to pain chronicity.

NAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice.

Acute injuries can progress into painful states that endure long after healing. The mechanisms underlying this transition remain unclear, but metabolic adaptations to the bioenergy demands imposed by injury are plausible contributors. Here we show that peripheral injury activates AKT/mTORC1 in afferent segments of the mouse spinal cord, redirecting local core metabolism toward biomass production while simultaneously suppressing autophagy-mediated biomass reclamation. This metabolic shift supports neuroplasticity, but creates a resource bottleneck that depletes critical spinal cord nutrients. Preventing this depletion with a modified diet normalizes biomass generation and autophagy and halts the transition to chronic pain. This effect, observed across multiple pain models, requires activation of the nutrient sensors, sirtuin-1 and AMPK, as well as restoration of autophagy. The findings identify metabolic reprogramming and consequent autophagy suppression as key drivers of the progression to pain chronicity and highlight nutritional and pharmacological interventions that could prevent this progression after surgery or other physical traumas.

Article	Year
Diet-Induced Obesity Disrupts Histamine-Dependent Oleoylethanolamide Signaling in the Mouse Liver. Pharmacology\| PubMed ID: 35691287	2022
Frequent Low-Dose Δ-Tetrahydrocannabinol in Adolescence Disrupts Microglia Homeostasis and Disables Responses to Microbial Infection and Social Stress in Young Adulthood. Biological psychiatry\| PubMed ID: 35750512	2022
Adolescent exposure to low-dose Δ9-tetrahydrocannabinol depletes the ovarian reserve in female mice. Toxicological sciences : an official journal of the Society of Toxicology\| PubMed ID: 36912754	2023
NAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice. Nature communications\| PubMed ID: 38402219	2024
Metabolic reprogramming in the spinal cord drives the transition to pain chronicity. bioRxiv : the preprint server for biology\| PubMed ID: 39975205	2025

Hye-Lim Lee

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