Participation of hypothalamic CB1 receptors in reproductive axis disruption during immune challenge

Abstract

It is known that immune challenge inhibits reproductive function and that endocannabinoids (eCB) modulate sexual hormones. However, no studies have been performed to assess whether the endocannabinoid system mediates the inhibition of hormones that control reproduction due to immune system activation during systemic infections. For that reason, we evaluated the participation of the hypothalamic cannabinoid receptor CB1 on hypothalamic-pituitary-gonadal (HPG) axis activity in rats submitted to immune challenge. Male adult rats were treated via intracerebroventricular (i.c.v.) administration with a CB1 antagonist/inverse agonist, (AM251, 500 ng/5 ul), followed by an intraperitoneal (i.p.) injection of lipopolysaccharide (LPS, 5 mg/kg) 15 min later. Plasmatic, hypothalamic and adenohypophyseal pro-inflammatory cytokines, hormones and neuropeptides were assessed 90 or 180 min post-LPS. Plasma concentration of TNFα and adenohypophyseal mRNA expression of Tnfα and Il1β increased 90 and 180 min post i.p. administration of LPS. However, cytokine mRNA expression in the hypothalamus increased only 180 min post-LPS, suggesting an inflammatory delay in this organ. CB1 receptor blockade with AM251 increased LPS inflammatory effects, particularly in the hypothalamus. LPS also inhibited the HPG axis by decreasing gonadotropin-releasing hormone (GnRH) hypothalamic content and plasma levels of luteinizing hormone (LH) and testosterone (T). These disruptor effects were accompanied by decreased hypothalamic Kiss1 mRNA expression and prostaglandin E2 (PGE2) content, as well as by increased gonadotropin-inhibitory hormone (Rfrp3) mRNA expression. All these disruptive effects were prevented by the presence of AM251. In summary, our results suggest that in male rats, eCB mediate immune challenge-inhibitory effects on reproductive axis at least partially via hypothalamic CB1 activation. In addition, this receptor also participates in homeostasis recovery, by modulating the inflammatory process taking place after LPS administration.

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