Background & Aims
Half of all patients with chronic pain have a comorbid anxiety or depressive disorder. Chronic stress often underlies these psychiatric disorders and can also amplify the experience of both acute and chronic pain. Chronic unpredictable stress (CUS), used as a model of depression in rodents, is known to lead to dendritic retraction and reduced spines in excitatory neurons of the prelimbic (PL) medial prefrontal cortex. PL projections to the ventrolateral periaqueductal gray (vlPAG) are involved in descending noxious inhibitory control, and activation of this circuit can modulate pain and anxiety-like behavior in nerve-injured animals. Chronic stress has been generally associated with hypofrontality, but it is not yet known whether the PL neurons projecting to vlPAG show changes in physiology due to stress, or whether changes to this circuit precipitate changes in pain behavior. The purpose of this study was to determine the role this circuit plays in stress-induced hypersensitivity.
Methods
We implemented a two-week model of CUS using pseudo-randomized stressors presented twice a day to male and female mice. Stress and control mice were subsequently subjected to one of several pain models, followed by a battery of pain and anxiety behavioral tasks. For electrophysiology experiments, mice were first injected with a retrograde fluorescent virus in the vlPAG. Then following stress or control conditions, we used whole-cell patch clamp electrophysiology to study intrinsic membrane and synaptic properties of back labeled cells in layer V of PL. In another experiment, we used a dual-viral approach to target PL-vlPAG neurons with designer receptors exclusively activated by designer drugs (DREADDs). CNO was administered prior to pain behavior to selectively activate PL-vlPAG neurons targeted with a Gq DREADD.
Results
Two weeks of CUS induced mechanical and thermal hypersensitivity and decreased pain tolerance in males but not female mice. Stressed males also showed prolonged differences in thermal hypersensitivity and anxiety-like behavior following injury. Two weeks of CUS did not change intrinsic membrane properties such as rheobase, action potential threshold, or resting membrane potential in vlPAG-projecting PL neurons. Finally, DREADD activation of the PL-vlPAG circuit in naïve mice increased pain tolerance in a thermal conflict assay. Results from additional experiments using DREADDs to manipulate the PL-vlPAG circuit during stress are pending.
Conclusions
Our results indicate that chronic stress promotes pain and anxiety-like behavior in male mice and prolongs the recovery from painful injury, which mirrors patient data in the literature. Stress appears to affect the activity of PL without changing the intrinsic excitability of output neurons projecting to vlPAG. The PL-vlPAG circuit, however, does play a role in some complex pain behaviors including pain tolerance. This information adds to our understanding of the complex neural circuitry that is involved in the processing of both pain and stress.
References
1.Yalcin I, Barrot M. The anxiodepressive comorbidity in chronic pain. Current Opinion in Anaesthesiology2014. p. 520-527.
2.Dahlhamer J, Lucas J, Zelaya, Carla, et al. Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults — United States, 2016. MMWR Morbidity and Mortality Weekly Report. 2018-09-14 2018;67(36):1001-1006. doi:10.15585/mmwr.mm6736a2
3.Vaegter HB, Andersen TE, Harvold M, Andersen PG, Graven-Nielsen T. Increased Pain Sensitivity in Accident-related Chronic Pain Patients With Comorbid Posttraumatic Stress. The Clinical Journal of Pain. 2018-04-01 2018;34(4):313-321. doi:10.1097/ajp.0000000000000543
4.Holmes A, Wellman CL. Stress-induced prefrontal reorganization and executive dysfunction in rodents. Neuroscience & Biobehavioral Reviews. 2009-06-01 2009;33(6):773-783. doi:10.1016/j.neubiorev.2008.11.005
5.16.Liu R-J, Aghajanian GK. Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: Role of corticosterone-mediated apical dendritic atrophy. Proceedings of the National Academy of Sciences. 2008-01-08 2008;105(1):359-364. doi:10.1073/pnas.0706679105
6.Huang J, Gadotti VM, Chen L, et al. A neuronal circuit for activating descending modulation of neuropathic pain. Nature Neuroscience. 2019-10-01 2019;22(10):1659-1668. doi:10.1038/s41593-019-0481-5
Presenting Author
Laura Maile
Poster Authors
Laura Maile
BSc
University of Cincinnati
Lead Author
Topics
- Mechanisms: Biological-Systems (Physiology/Anatomy)