Background & Aims
In previous research demonstrated that repeated paring of pain stimuli with external conditioned stimuli (such as sounds or visual stimuli), leads to conditioned hyperalgesia both in mice and humans (1, 2). In this study we developed a new model to induce conditioned hyperalgesia in mice that can be particularly relevant for surgery settings. Moreover, we investigated the neurochemical mediation of this phenomenon with a focus on cholecystokinin (CCK), a neurotransmitter that has previously been demonstrated to affect nocebo hyperalgesia in humans (3).
Methods
A conditioning paradigm with one training and one test day was used. On the training day, following the determination of mechanical pain sensitivity (von Frey test), mice underwent a paw incision surgery (incision of skin, underlying fascia and muscle). After the surgery mice were immediately placed in a conditioned context and kept there for 6 hours when the post-surgical pain is expected to be the highest. On the test day, 6 says after the surgery, mice were re-tested for mechanical pain sensitivity either in the same or in a different context. In separate set of experiments, mice were randomly assigned to one of the two drug conditions: CCK-B antagonist LY-225910 (1 mg/kg) or saline. Drugs were administered immediately before the surgery on the training day and at the start of the test day.
Results
A significant increase in pain sensitivity was observed in mice tested in the same context, compared to the different context condition, indicating conditioned hyperalgesia. Mice in the same context still demonstrated higher levels of pain sensitivity after the surgery, while mice in the different context, had no heightened pain sensitivity. This conditioned hyperalgesia was blocked by LY-225910. The drug had no effect on pain.
Conclusions
We have demonstrated that post-surgical pain can be conditioned by a single exposure with a context, and that this conditioned hyperalgesia is still present 6 days after the surgery. LY-225910 blocks conditioned hyperalgesia in mice, indicating that CCK-B receptors are involved in mediating this phenomenon. CCK-B receptors are distributed primarily in the central nervous system and CCK-B has various psychophysiological functions, such as regulation of anxiety and memory.
References
1. Martin LJ, Acland EL, Cho C, Gandhi W, Chen D, Corley E, Kadoura B, Levy T, Mirali S, Tohyama S, Khan S. Male-specific conditioned pain hypersensitivity in mice and humans. Current Biology. 2019 Jan 21;29(2):192-201.
2. Petersen GL, Finnerup NB, Colloca L, Amanzio M, Price DD, Jensen TS, Vase L. The magnitude of nocebo effects in pain: a meta-analysis. Pain®. 2014 Aug 1;155(8):1426-34.
3. Benedetti F, Amanzio M, Vighetti S, Asteggiano G. The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect. Journal of Neuroscience. 2006 Nov 15;26(46):12014-22.
Presenting Author
Aleksandrina Skvortsova
Poster Authors
Topics
- Mechanisms: Biological-Systems (Physiology/Anatomy)