The Old and the New: Cardiovascular and Respiratory Alterations Induced by Acute JWH-018 Administration Compared to Δ9-THC—A Preclinical Study in Mice

Abstract

Several new psychoactive substances (NPS) are responsible for intoxication involving the cardiovascular and respiratory systems. Among NPS, synthetic cannabinoids (SCs) provoked side effects in humans characterized by tachycardia, arrhythmias, hypertension, breathing difficulty, apnoea, myocardial infarction, and cardiac arrest. Therefore, the present study investigated the cardio-respiratory (MouseOx Plus; EMKA electrocardiogram (ECG) and plethysmography TUNNEL systems) and vascular (BP-2000 systems) effects induced by 1-naphthalenyl (1-pentyl-1H-indol-3-yl)-methanone (JWH-018; 0.3–3–6 mg/kg) and Δ9-tetrahydrocannabinol (Δ9-THC; 0.3–3–6 mg/kg), administered in awake CD-1 male mice. The results showed that higher doses of JWH-018 (3–6 mg/kg) induced deep and long-lasting bradycardia, alternated with bradyarrhythmia, spaced out by sudden episodes of tachyarrhythmias (6 mg/kg), and characterized by ECG electrical parameters changes, sustained bradypnea, and systolic and transient diastolic hypertension. Otherwise, Δ9-THC provoked delayed bradycardia (minor intensity tachyarrhythmias episodes) and bradypnea, also causing a transient and mild hypertensive effect at the tested dose range. These effects were prevented by both treatment with selective CB1 (AM 251, 6 mg/kg) and CB2 (AM 630, 6 mg/kg) receptor antagonists and with the mixture of the antagonists AM 251 and AM 630, even if in a different manner. Cardio-respiratory and vascular symptoms could be induced by peripheral and central CB1 and CB2 receptors stimulation, which could lead to both sympathetic and parasympathetic systems activation. These findings may represent a starting point for necessary future studies aimed at exploring the proper antidotal therapy to be used in SCs-intoxicated patient management.

Acute Cardiovascular and Cardiorespiratory Effects of JWH-018 in Awake and Freely Moving Mice: Mechanism of Action and Possible Antidotal Interventions?

“…It is well known that CB1 receptor binding is the main cause of the effects induced by JWH-018 in preclinical models. In fact, numerous previous studies have shown that pretreatment with AM-251 prevented these effects [21,30], thus confirming the involvement of CB1 receptors that are highly expressed in CNS of rodents [31]. Centrally, CB1 receptors can also modulate cardiac and vascular functions involving the medulla and dorsal periaqueductal gray (dPAG) [32,33].…”

“…Even bradycardic and hypotensive responses have been reported after SCs assumption, especially among the third-generation SCs [12,14,20]. Preclinical in vivo studies mainly revealed that synthetic cannabinoid-induced effects are bradycardia, bradyarrhythmias with sudden tachyarrhythmias, hypertension, and bradypnea [19], as our recent JWH-018 study also demonstrated [21]. Moreover, previous studies in rodents confirmed these effects after JWH-018 administration [22,23] as well as after administration of other SCs (i.e., CP-55,920 or AKB48) [24,25].…”

“…The role of CB2 receptors in the mechanisms underlying the effects induced by SCs in mice has been shown [21]. In fact, CB2 receptor selective antagonist, AM 630, reverted CV and respiratory effects of JWH-018 in a different manner from AM 251 [21]. In line with these findings, preclinical and clinical data state that CB receptors are G protein-coupled receptors involved in cognitive, cardiovascular, and metabolic functions.…”

“…As shown in most recent research, modulation of CB1 and CB2 receptors could lead to interaction with ion channels [21,38]. Every phase of the cardiac reaction is regulated by voltage-and ligand-gated ion channels, which can be implicated in many types of arrhythmias due to, for instance, autonomic nervous system overstimulation or electrolyte imbalance [39].…”

“…Centrally, CB1 receptors can also modulate cardiac and vascular functions involving the medulla and dorsal periaqueductal gray (dPAG) [32,33]. The role of CB2 receptors in the mechanisms underlying the effects induced by SCs in mice has been shown [21]. In fact, CB2 receptor selective antagonist, AM 630, reverted CV and respiratory effects of JWH-018 in a different manner from AM 251 [21].…”