Concentration-Dependent Effects of the Endocannabinoid 2-Arachidonoylglycerol on Nociceptive and Non-Nociceptive Synapses.

Burrell B. · Journal of neurophysiology · 2026

**Background & Methods** This review examined the concentration-dependent effects of 2-arachidonoylglycerol (2-AG), an endogenous cannabinoid, on nociceptive and non-nociceptive synapses using the medicinal leech (Hirudo verbana) model. The study compared 2-AG concentrations ranging from 0.001 to 200 µM on synapses formed by nociceptive (N) and pressure-sensitive (P) afferents, with receptor antagonists (CB1 blocker AM251 and TRPV1 inhibitor SB366792) used to identify mechanism of action. **Key Findings** • 2-AG demonstrated a biphasic concentration profile with distinct effects at low (~0.01 µM) and high (~100 µM) concentration ranges, while an intermediate range (~1 µM) produced no significant synaptic changes. This suggests potential for concentration-selective therapeutic targeting. • Low-concentration 2-AG effects (depression of nociceptive synapses and potentiation of non-nociceptive synapses) were selectively blocked by CB1 antagonism, indicating CB1 receptor-mediated mechanisms independent of TRPV1 pathways. • High-concentration 2-AG effects required both CB1 and TRPV1 receptor inhibition for blockade, indicating engagement of dual receptor pathways at elevated concentrations. Elevation of endogenous 2-AG via MAGL inhibition (using MJN110) reproduced the CB1-dependent effects without TRPV1 involvement. **Dosage & Administration** 2-AG concentrations tested: 0.001–200 µM. Pharmacological modulators used: AM251 (CB1 reverse agonist) and SB366792 (TRPV1 inhibitor). MJN110 was used as a MAGL inhibitor to increase endogenous 2-AG levels. Specific administration routes and dosing schedules not reported. **Safety & Adverse Effects** Not reported. This was a basic neuroscience research study examining synaptic mechanisms in an invertebrate model; clinical safety data were not assessed. **Evidence Quality** This is a mechanistic review study with significant limitations for clinical translation. Use of the medicinal leech, while valuable for synaptic analysis, has limited relevance to mammalian pain pathways. The finding that opposing pro- and anti-nociceptive effects occur at similar concentration ranges, separated only by an intermediate "silent" range, raises concerns about therapeutic selectivity. The biphasic response profile and dual receptor involvement (CB1 and TRPV1) complicate development of targeted cannabinoid therapies. Evidence level: Preclinical basic science research.

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