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

Abstract The endocannabinoid system is important for pain modulation, whereas its utilization for analgesia is restricted due to the limited efficacy of cannabinoids and side effects. Cannabinoid receptor 1 (CB 1 ) in the spinal dorsal horn provides presynaptic inhibition of nociceptive neurotransmission. CB 1 regulatory protein, SH3‐containing GRB2‐like protein 3‐interacting protein 1 (SGIP1), controls its functional availability, while its role in pain modulation remains poorly understood. We examined the role of SGIP1 in nociceptive signalling under control and inflammatory conditions, using behavioural tests, patch‐clamp recordings in spinal cord slices and calcium imaging of dorsal root ganglion (DRG) neurons. SGIP1 knockout (KO) mice of both sexes showed a selective reduction in heat sensitivity, with no change in mechanical withdrawal threshold. Following carrageenan‐induced inflammation, both wild‐type (WT) and KO mice developed mechanical allodynia, whereas thermal hyperalgesia in KO mice reached only the control values of WT mice. Intrathecal application of cannabinoid agonist WIN55,212‐2 produced analgesia in both WT and KO mice, with enhanced effect of the lower dose (5 µg vs . 10 µg) in KO animals. WIN55,212‐2 (1 µM) in slices from inflamed SGIP1 KO mice induced significantly greater reduction in miniature excitatory postsynaptic current (mEPSC) frequency, without amplitude change, indicating enhanced presynaptic inhibition in KO mice. These enhanced inhibitory effects of WIN55,212‐2 in KO mice after inflammation were further demonstrated in DRG cultured neurons. Our results establish SGIP1 as a state‐dependent negative modulator of CB 1 function and identify SGIP1–CB 1 interaction as a candidate target for selective enhancement of cannabinoid analgesia under inflammatory pain conditions. image Key points SGIP1 deletion reduced basal heat sensitivity in mice of both sexes without altering mechanical threshold, suggesting a sex‐independent role in thermal nociception. Inflammation increased mechanical and thermal sensitivity in both SGIP1 KO and WT mice, whereas the increased thermal sensitivity of KO reached only the baseline levels of WT mice. Intrathecal cannabinoid agonist WIN55,212‐2 produced analgesia in both genotypes, with a bigger effect of the lower dose (5 vs . 10 µg) in SGIP1 KO mice. WIN55,212‐2 induced strong inhibition of miniature excitatory postsynaptic current (mEPSC) frequency in dorsal horn neurons that was selectively potentiated by SGIP1 deletion under inflammatory, but not control, conditions, consistent with a presynaptic locus of action. These effects were further confirmed by calcium imaging in DRG cultured neurons. SGIP1 acts as an inflammation‐dependent presynaptic CB 1 modulator of spinal nociceptive transmission, positioning the SGIP1–CB 1 interaction as a candidate target for selective enhancement of cannabinoid analgesia.