Posted on 28-02-2019

Conditioned pain modulation is not unidirectional: both hyper- and hypoalgesia can arise depending on the stimulus


Conditioned pain modulation (CPM) is the phenomenon in which one painful stimulus (the conditioning stimulus) affects the pain perception of a second stimulus (the test stimulus) at a different site. Hypoalgesic CPM, in which the conditioning stimulus reduces pain response to the test stimulus, is known as diffuse noxious inhibitory control (DNIC), or simply put – “pain inhibits pain”. However, numerous human studies have found highly variable and contradictory results to DNIC, where some observe hypoalgesia after conditioned stimulus and others show hyperalgesia. To understand the variability of CPM response a team led by Dr. Jeffrey Mogil, in collaboration with UTCSP scientist Dr. Loren Martin, used rodent models to systematically test the effects of CPM using multiple conditioning and test stimuli.


Using CD-1 mice given acetic acid as the conditioning stimulus, they observed hyperalgesia in response to thermal and mechanical test stimuli, contradicting DNIC. This controversial observation was reproduced in DBA/2J mice and Sprague-Dawley rats, and also using a different conditioning stimulus – orofacial formalin. They next showed that increasing the intensity of the conditioning stimulus (i.e., increased acetic acid concentration) only exacerbated the hyperalgesic response to the test stimuli.

Nonetheless, hypoalgesic CPM (or DNIC) was observed under some scenarios: mice given a highly noxious test stimulus were more tolerant. For example, while acetic acid injection in mice increased their sensitivity to 46oC (low-intensity thermal stimulus), it reduced their sensitivity to 52oC (high-intensity). Hypoalgesia from CPM was also observed after peripheral nerve injury, where neuropathic mice showed higher tolerance to mechanical test stimuli after receiving an acetic acid conditioning stimulus.

The results of this study suggest that the effects of CPM are dependent on test stimulus intensity and can be bidirectional, resulting in either a hyperalgesic or hypoalgesic effect. This paper also demonstrates that fully understanding a phenomenon requires studying it under varying conditions.

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Reference: Tansley, S.N., Macintyre, L.C., Diamond, L., Sotocinal, S.G., George, N., Meluban, L., Austin, J.-S., Coderre, T.J., Martin, L.J., and Mogil, J.S. (2018). Conditioned pain modulation in rodents can feature hyperalgesia or hypoalgesia depending on test stimulus intensity. Pain.