SGIP1 limits cannabinoid receptor signalling in spinal nociceptive synapses and modulates analgesia during neuroinflammation.

Dresslerova D.; Pontearso M.; Muzik D.; Bhattacharyya A.; Slepicka J.; Vasconcelos D.; Palecek J.; Spicarova D. · The Journal of physiology · 2026

**Background & Methods** This study investigated the role of SGIP1 (SH3-containing GRB2-like protein 3-interacting protein 1) in cannabinoid-mediated pain modulation using SGIP1 knockout (KO) and wild-type (WT) mice of both sexes. The research employed behavioral pain tests, patch-clamp electrophysiology recordings from spinal cord slices, and calcium imaging of dorsal root ganglion neurons under control and carrageenan-induced inflammatory conditions. **Key Findings** • SGIP1 knockout mice demonstrated selective reduction in heat sensitivity without changes in mechanical withdrawal threshold under basal conditions, with this effect occurring equally in both sexes. Following carrageenan-induced inflammation, KO mice showed attenuated thermal hyperalgesia compared to WT mice, though both groups developed mechanical allodynia. • Intrathecal administration of cannabinoid agonist WIN55,212-2 produced analgesia in both genotypes, with notably enhanced efficacy of the lower 5 μg dose in SGIP1 KO mice compared to the 10 μg dose, suggesting improved cannabinoid sensitivity with SGIP1 deletion. • Electrophysiological recordings revealed that WIN55,212-2 induced significantly greater reduction in miniature excitatory postsynaptic current (mEPSC) frequency in spinal dorsal horn neurons from inflamed SGIP1 KO mice without affecting amplitude, indicating enhanced presynaptic inhibition of nociceptive transmission. These findings were corroborated by calcium imaging experiments in cultured dorsal root ganglion neurons. **Dosage & Administration** Intrathecal WIN55,212-2 doses: 5 μg and 10 μg. In vitro electrophysiology: 1 μM WIN55,212-2. **Safety & Adverse Effects** Not reported. **Evidence Quality** This is a preclinical animal study with controlled experimental conditions and multiple complementary methodologies (behavioral, electrophysiological, and imaging), strengthening internal validity. Limitations include restriction to animal models without human clinical data, single inflammatory model (carrageenan), and limited exploration of potential off-target effects of SGIP1 deletion. The sex-independent effects across both male and female mice enhance generalizability within rodent models. The inflammation-dependent enhancement of cannabinoid efficacy represents an important mechanistic finding but requires clinical translation to establish therapeutic relevance.

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