Background & Aims

Chronic pain and alcohol use disorder are both widespread health concerns. Individuals often resort to alcohol as a form of self-medication for chronic pain, and persistent pain is frequently reported among those with alcohol use disorder. Despite the high prevalence of chronic pain and alcohol use disorder, little is known about the neural mechanisms underlying this comorbidity. Here, the interplay between chronic ethanol consumption and persistent pain was investigated using a mouse model of nerve injury-induced hypersensitivity. We tested the hypothesis that chronic alcohol exposure increases the duration of recovery from mechanical hypersensitivity.

Methods

Chronic intermittent ethanol two-bottle choice: Singly-housed mice drank from two bottles—one with 20% ethanol and the other water. Daily recording of bottle weights tracked fluid intake. The regimen alternated 24-hour access and withdrawal periods, lasting 8-12 weeks from drinking onset. Measurement of mechanical withdrawal thresholds: Mice acclimated for two hours before testing on wire mesh platforms in individual enclosures. Von Frey monofilaments were sequentially applied to hind paw surfaces to determine 50% withdrawal thresholds via the UpDown method. Nerve injury-induced hypersensitivity: Sciatic nerve crush surgery involved a mid-thigh incision, dissection of the hamstring muscle and exposure of the sciatic nerve. Fine hemostatic forceps crushed the entire diameter of the nerve for 15s. Intrathecal injections: Awake mice received intrathecal injections of either 150ng of gabazine or vehicle via lumbar puncture. Immunohistochemistry: Brain and spinal cord tissue underwent IHC.

Results

Chronic alcohol exposure resulted in mechanical hypersensitivity in alcohol-drinking mice compared to water-drinking mice approximately 4-5 weeks after drinking initiation. This alcohol-induced hypersensitivity was attenuated by the selective inhibitor of GABA receptors, gabazine. In contrast, gabazine produced hypersensitivity in uninjured water-drinking mice. After sciatic nerve injury recovery of mechanical withdrawal thresholds to pre-injury levels was delayed in alcohol drinkers compared to water-consuming mice. Specifically, water-drinking mice recovered to pre-surgical thresholds 5 weeks after injury, while alcohol-drinking animals exhibited delayed and partial recovery at that time point. Immunohistochemistry on brain and spinal cord tissue from these mice suggested that alcohol-drinking nerve-injured mice have increased neural activation, assessed by c-fos expression, in numerous brain regions relevant to reward and pain circuitry, including the DRN, PAG, mPFC, and BLA.

Conclusions

The observed alterations in pain sensitivity associated with chronic alcohol may be attributed to dysregulation within descending pain circuitry, possibly through descending modulation of spinal pain processing mediated in part by changes in spinal GABA signaling. Overall, these findings suggest chronic voluntary alcohol consumption prolongs the duration of recovery of tactile hypersensitivity in a nerve injury-induced hypersensitivity model.

References

[1] Yeung, E. W., Craggs, J. G., & Gizer, I. R. (2017). Comorbidity of Alcohol Use Disorder and Chronic Pain: Genetic Influences on Brain Reward and Stress Systems. Alcoholism, clinical and experimental research, 41(11), 1831–1848. https://doi.org/10.1111/acer.13491
[2] Egli, M., Koob, G. F., & Edwards, S. (2012). Alcohol dependence as a chronic pain disorder. Neuroscience and biobehavioral reviews, 36(10), 2179–2192. https://doi.org/10.1016/j.neubiorev.2012.07.010
[3] Maleki, N., Tahaney, K., Thompson, B. L., & Oscar-Berman, M. (2019). At the intersection of alcohol use disorder and chronic pain. Neuropsychology, 33(6), 795–807. [Electronic version]. Retrieved from https://doi.org/10.1037/neu0000558.
[4] Apkarian, A. V., Neugebauer, V., Koob, G., Edwards, S., Levine, J. D., Ferrari, L., Egli, M., & Regunathan, S. (2013). Neural mechanisms of pain and alcohol dependence. Pharmacology, biochemistry, and behavior, 112, 34–41. https://doi.org/10.1016/j.pbb.2013.09.008
[5] Guenthner, C.J., Miyamichi, K., Yang, H.H., Heller, H.C., Luo, L. (2013). Permanent genetic access to transiently active neurons via TRAP: targeted recombination in active populations. Neuron, 78(5), 773-84. [Electronic version]. doi: 10.1016/j.neuron.2013.03.025.

Presenting Author

Rachel E. Schorn

Poster Authors

Rachel Schorn

BSc

University of Minnesota Twin Cities

Lead Author

E-mail

Maureen S. Riedl PhD

University of Minnesota Twin Cities

Lead Author

E-mail

Kelley F. Kitto

University of Minnesota, Dept. of Pharmaceutics

Lead Author

E-mail

L. Stone

University of Minnesota Twin Cities

Lead Author

E-mail

Anna M. Lee PhD

University of Minnesota Twin Cities

Lead Author

E-mail

Topics

  • Models: Chronic Pain - Neuropathic