Synthetic cannabinoids and the purinergic–dopaminergic axis: P2X7 as a primary sensor of neuroinflammatory injury and the role of adenosine receptor heteromers in emerging NPS toxicity

Abstract

Synthetic cannabinoids (SCs), marketed as Spice, K2, and dozens of successor compounds, constitute one of the most pharmacologically dangerous categories of new psychoactive substances (NPS) currently in circulation. Their extreme toxicity relative to Δ9-tetrahydrocannabinol (THC) cannot be explained by CB1 receptor pharmacokinetics alone. This review proposes that the purinergic signaling system, specifically the P2X7 receptor and the adenosine receptor heteromers A2A–D2 and A1–D1, constitutes the central molecular amplifier of SC-induced neurotoxicity, operating downstream of CB1 superagonism but upstream of the neurological phenotypes that define acute SC poisoning. Full CB1 agonism collapses retrograde synaptic suppression, unleashing glutamatergic excitotoxicity and mitochondrial dysfunction that release massive quantities of extracellular ATP as a damage-associated molecular pattern (DAMP). P2X7, acting as the primary cellular sensor of this ATP surge, initiates NLRP3 inflammasome assembly, caspase-1 activation, and IL-1β secretion, establishing a self-sustaining neuroinflammatory cycle in the striatum and cortex. Simultaneously, the ectonucleotidase-mediated conversion of excess ATP to adenosine floods A2A receptors on striatopallidal neurons, allosterically reducing D2 receptor affinity for dopamine through the constitutive A2A–D2 heterodimer — directly suppressing dopaminergic motor tone and contributing to the psychomotor arrest clinically described as the zombie effect. The A1–D1 heteromer in the direct pathway adds a complementary layer of inhibition. Together, these purinergic–dopaminergic molecular interactions translate CB1 superagonism into the distinctive and dangerous clinical phenomenology of SC intoxication in ways that classical cannabinoid pharmacology does not predict. Pharmacological implications include the potential repositioning of P2X7 antagonists and A2A receptor antagonists as interventions for acute SC poisoning, and the necessity of integrating purinergic endpoints into toxicological profiling of emerging NPS compounds.