Injecting substance P into the spinal cord of mice temporarily caused a behavioral syndrome but no lasting toxic effects or changes in pain sensitivity measured by tail-flick response to heat. However, when given 30 minutes later, the pain-suppressing effect of the serotonin receptor agonist 5-MeODMT was markedly reduced. Skin temperatures were nearly identical between substance P and control groups, ruling out temperature changes as a confound. These results indicate a functional interaction between substance P and serotonin in spinal pain processing, suggesting that intrathecal substance P modulates serotonin receptor function.
Repeated administration of the psychedelic compound 5-MeODMT in mice reduces its own pain-killing effect and that of a related drug, 8-OH-DPAT, in tail-flick and hot-plate tests. The behavioral responses to spinal injections of serotonin and substance P—vigorous biting, licking, and scratching—were also weakened after repeated 5-MeODMT treatment. The findings suggest that repeated 5-MeODMT downregulates serotonin receptors involved in pain relief, and the rapid desensitization to both serotonin and substance P may indicate a functional interaction between these two signaling molecules in the spinal cord's modulation of pain.