Cannabinoid actions in a nonsurgical mouse model of sensitized dural nociceptors.

Kitaoka Y.; Whyland K.; Li Z.; Koshika K.; Yamamoto T.; Mulpuri Y.; Spigelman I. · Pain · 2026

**Background & Methods** This experimental study examined peripherally restricted cannabinoids (PRCBs) in a mouse model of dural acid-induced hypersensitivity. Female C57BL/6J mice received supradural injections of pH-6.0 saline to induce periorbital allodynia, with pain assessed using von Frey filaments and electrophysiological recordings from dural trigeminal ganglion neurons. **Key Findings** • Supradural pH-6.0 saline induced periorbital allodynia in mice by 48 hours, and by 72 hours, these sensitized mice developed latent hypersensitivity (elicited with pH-7.0 saline). Coadministration of the dual CB1R/CB2R agonist PrNMI or the CB1R-selective agonist ACEA with pH-6.0 prevented both initial and latent allodynia, whereas the CB2R-selective agonist RNB61 had no preventative effect. • Selective inverse agonists for CB1R or CB2R abolished PrNMI's preventative effects, indicating that coactivation of both receptors is required for analgesia. Once allodynia was established, combined CB1R/CB2R activation (pH-7.0/PrNMI) failed to reverse latent hypersensitivity. • Patch-clamp recordings demonstrated that PrNMI suppressed acid-induced depolarizations in dural trigeminal neurons from control mice but not from pH-6.0-pretreated (sensitized) mice, whereas CB2R activation alone had no electrophysiological effect on nociceptor function. **Dosage & Administration** PrNMI: 5 µM (supradural coadministration with saline); ACEA: 5 µM (supradural); RNB61: 5 µM and 0.5 µM (supradural and patch-clamp, respectively); Supradural injection volume: 4.5 µL. **Safety & Adverse Effects** The study emphasizes that peripherally restricted cannabinoids exhibit analgesic efficacy with "minimal CNS side effects" compared to centrally penetrant CB1R agonists, but specific adverse events were not reported in this experimental model. **Evidence Quality** This is a mechanistic preclinical study with significant limitations: findings are restricted to a single animal model and sex (female mice), lack human validation, and involve acute experimental pain induction rather than chronic pathological pain. The study provides valuable insights into receptor selectivity requirements for cannabinoid analgesia but cannot directly inform clinical application. Evidence quality is moderate for basic neuroscience research but insufficient for clinical translation without further studies.

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