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.
In rats, destroying spinal norepinephrine (NA) neurons with 6-hydroxydopamine eliminated the pain-relieving effect of the serotonin receptor agonist 5-MeODMT in three different pain tests. Replacing NA directly into the spinal cord restored the analgesic effect. Chemical analysis confirmed a 95% loss of NA in the spinal cord. Destroying serotonin neurons with 5,7-DHT reduced the analgesic effect in one test. The findings show that NA is necessary for 5-MeODMT to produce analgesia and further clarify how NA modulates serotonin-related pain relief.