Synthetic Cannabinoids and the Purinergic–Dopaminergic Axis: P2x7 as a Candidate Primary Sensor of Neuroinflammatory Injury and the Role of Adenosine Receptor Heteromers in Emerging Nps Toxicity—A Hypothesis-Driven Integrative Review

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) is not fully accounted for by CB1 receptor pharmacokinetics alone. This review proposes an integrative mechanistic framework—presented as a hypothesis-driven model rather than an established causal chain—in which the purinergic signaling system, and specifically the P2X7 receptor together with the adenosine A2A–D2 and A1–D1 receptor heteromers, is proposed as a candidate central molecular amplifier of SC-induced neurotoxicity, operating downstream of CB1 superagonism and upstream of the neurological phenotypes that define acute SC poisoning. The proposed pathway is built around four convergent steps whose empirical support is uneven and is assigned throughout the manuscript to one of three epistemic strata: (i) experimentally demonstrated observations from SC models; (ii) mechanistically supported inferences drawn from adjacent experimental systems; and (iii) hypothesis-generating components whose validation remains prospective. The steps are: (a) full CB1 agonism destabilizes the retrograde endocannabinoid feedback architecture through rapid desensitization, circuit-specific disinhibition, and off-target polypharmacology, permitting net glutamatergic escalation; (b) NMDA-mediated excitotoxicity and mitochondrial injury release supraphysiological extracellular ATP; (c) P2X7, acting as a candidate high-threshold damage sensor, is proposed to initiate NLRP3 inflammasome assembly and IL-1β secretion, establishing a self-sustaining neuroinflammatory cycle; and (d) ectonucleotidase-mediated conversion of ATP to adenosine is proposed to allosterically suppress D2 and D1 responsiveness through the constitutive A2A–D2 and A1–D1 heteromers, potentially contributing to the psychomotor arrest clinically described as the zombie phenotype. Pharmacological implications include the identification of P2X7 antagonists, NLRP3 inhibitors, and selective A2A antagonists as mechanistically motivated experimental targets whose validation in SC toxicity models remains a research priority.