LAUSR

&NA; Repetitive activation of non‐nociceptive afferents is known to attenuate nociceptive signaling. However, the functional details of how this modulatory process operates are not understood and this has been a barrier in using such stimuli to effectively treat chronic pain. The present study tests the hypothesis that the ability of repeated non‐nociceptive stimuli to reduce nociception is a form of generalized habituation from the non‐nociceptive stimulus‐response pathway to the nociceptive pathway. Habituation training, using non‐nociceptive mechanosensory stimuli, did reduce responses to nociceptive thermal stimulation. This generalization of habituation to nociceptive stimuli required endocannabinoid‐mediated neuromodulation, although disrupting of endocannabinoid signaling did not affect “direct” habituation of to the non‐nociceptive stimulus. Surprisingly, the reduced response to nociceptive stimuli following habituation training was very long‐lasting (3–8 days). This long‐term habituation required endocannabinoid signaling during the training/acquisition phase, but endocannabinoids were not required for post‐training retention phase. The implications of these results are that applying principles of habituation learning could potentially improve anti‐nociceptive therapies utilizing repeated non‐nociceptive stimulation such as transcutaneous nerve stimulation (TENS), spinal cord stimulation (SCS), or electro‐acupuncture.