How does THC reduce pain at the molecular level?

THC reduces pain through multiple mechanisms. Primary: partial agonism at CB1 receptors in the dorsal horn of the spinal cord inhibits nociceptive signal transmission by reducing presynaptic glutamate and substance P release. Secondary: CB1 activation in the periaqueductal gray (PAG) activates descending inhibitory pathways. Peripheral CB1 and CB2 receptors on nociceptors reduce peripheral sensitization. THC also activates TRPV1 channels (causing initial activation then desensitization) and modulates opioid receptor signaling. The analgesic effect is dose-dependent and subject to tolerance via CB1 receptor downregulation with chronic use.