Background & Aims

Alcohol Use Disorder (AUD) is a chronic medical condition known to be comorbid with acute pain. For example, we recently reported that 4 weeks of chronic intermittent ethanol vapor in male and female C57BL/6J (B6J) mice was associated with mechanical and heat hypersensitivity when tested up to 48 hours after its cessation. We coined the term “chronic alcohol withdrawal induced pain (CAWIP)” to describe this model. The current studies were designed to test the hypotheses that CAWIP transitions to states of: 1) extended withdrawal; and 2) chronic pain.

Methods

Sensitivity to mechanical (von Frey) and heat (hotplate) at the plantar skin was measured at 1, 2, 3, 7, 14, 21, 28, and 35 days after cessation of 4 weeks of chronic intermittent ethanol vapor (CIEV) to determine the duration of mechanical and heat hypersensitivity in CAWIP. Conditioned place preference (CPP) to three days of gabapentin (100 mg/kg i.p.) was completed 4 days after cessation of CIEV. Next, we determined whether chronic alcohol causes latent pain sensitization that can be unmasked with pharmacological administration of opioid receptor antagonist / inverse agonists, as we have observed in other models of chronic pain. To address the question, we waited for the resolution of CAWIP, administered naltrexone (NTX; 3 mg/kg s.c.), and then evaluated: 1) mechanical and heat sensitivity at 30, 60, 90, and 120 minute timepoints; and 2) conditional place aversion (CPA).

Results

Both male (n=8) and female (n=8) B6J mice demonstrated mechanical hypersensitivity that peaked at 24-48 hour after cessation of CIEV. 4 days after CIEV, CPP to the gabapentin-paired chamber was exhibited by female mice (n=4, P=0.004). Remarkably, mechanical hypersensitivity persisted for three additional weeks in a pain state that we term extended withdrawal. Heat hypersensitivity did not continue into extended withdrawal as it was never seen in males and persisted for only three days in females. After the resolution of extended withdrawal (4 weeks after cessation of CIEV), NTX caused a profound reinstatement of mechanical hypersensitivity in female (n=8, P=0.002), but not male mice (n=8). Lastly, female mice exhibited a trend towards CPA to the NTX paired chamber (n=4, P=1.175), however, small subject size precludes a definitive answer.

Conclusions

We found that mechanical hypersensitivity persisted in males and females for 3 weeks after cessation of alcohol; this extended withdrawal indicates that chronic alcohol produces a long-lasting dependence. Mechanical hypersensitivity could only be reinstated with naltrexone in females; these data suggest that latent sensitization is sex dependent. Gabapentin caused place preference in females but not males; these results demonstrate that chronic alcohol causes aversion upon its cessation and promotes gabapentin for the treatment of CAWIP. We are currently conducting Ca2+ recordings with fiber photometry in the parabrachial nucleus (PBN) to determine whether it mediates hypersensitivity during early and extended withdrawal and during latent sensitization. Future studies will determine the neurochemical signaling mechanisms of chronic alcohol-associated latent sensitization and its inhibition by G protein-coupled receptors.

References

Egli M, Koob GF, Edwards S. Alcohol dependence as a chronic pain disorder. Neuroscience & Biobehavioral Reviews. 2012;36(10):2179-2192. doi:10.1016/j.neubiorev.2012.07.010

Brandner A, Baratta A, Rathod R, Ferguson C, Taylor B, Farris S. Mechanical and Heat Hyperalgesia upon Withdrawal from Chronic Intermittent Ethanol Vapor depends on Sex, Exposure Duration, and Blood Alcohol Concentration in Mice. The Journal of Pain. Published online March 1, 2023. doi:10.1016/j.jpain.2023.02.024

Corder G, Doolen S, Donahue RR, Winter MK, Jutras BL, He Y, Hu X, Wieskopf JS, Mogil JS, Storm DR, Wang ZJ, McCarson KE, Taylor BK. Constitutive ?-Opioid Receptor Activity Leads to Long-Term Endogenous Analgesia and Dependence. Science. 2013;341(6152):1394-1399. doi:10.1126/science.1239403

Presenting Author

Adam Brandner

Poster Authors

Adam Brandner

BSc

University of Pittsburgh

Lead Author

E-mail

Topics

  • Mechanisms: Biological-Systems (Physiology/Anatomy)