Binge Ethanol Consumption Increases Inflammatory Pain Responses and Mechanical and Cold Sensitivity: Tigecycline Treatment Efficacy Shows Sex Differences

Abstract

BackgroundPhysicians have long reported that patients with chronic pain show higher tendencies for alcohol use disorder (AUD), and AUD patients appear to have higher pain sensitivities. The goal of this study was to test 2 hypotheses: (i) binge alcohol consumption increases inflammatory pain and mechanical and cold sensitivities; and (ii) tigecycline is an effective treatment for alcohol‐mediated‐increased pain behaviors and sensitivities. Both female and male mice were used to test the additional hypothesis that important sex differences in the ethanol (EtOH)‐related traits would be seen.Methods“Drinking in the Dark” (DID) alcohol consuming and nondrinking control, female and male, adult C57BL/6J mice were evaluated for inflammatory pain behaviors and for the presence of mechanical and cold sensitivities. Inflammatory pain was produced by intraplantar injection of formalin (10 μl, 2.5% in saline). For cold sensation, a 20 μl acetone drop was used. Mechanical withdrawal threshold was measured by an electronic von Frey anesthesiometer. Efficacy of tigecycline (80 mg/kg i.p.) to reduce DID‐related pain responses and sensitivity was tested.Results DID EtOH consumption increased inflammatory pain behavior, while it also produced sustained mechanical and cold sensitivities in both females and males. Tigecycline produced antinociceptive effects in males; a pro‐nociceptive effect was seen in females in the formalin test. Likewise, the drug reduced both mechanical and cold sensitivities in males, but females showed an increase in sensitivity in both tests.ConclusionsOur results demonstrated that binge drinking increases pain, touch, and thermal sensations in both sexes. In addition, we have identified sex‐specific effects of tigecycline on inflammatory pain, as well as mechanical and cold sensitivities. The development of tigecycline as an AUD pharmacotherapy may need consideration of its pro‐nociceptive action in females. Further studies are needed to investigate the mechanism underlying the sex‐specific differences in nociception.

Effective Reduction of Acute Ethanol Withdrawal by the Tetracycline Derivative, Tigecycline, in Female and Male DBA/2J Mice

“…There was no effect of tigecycline on blood alcohol elimination, which was expected as we had not previously detected a change in the pharmacokinetic elimination of alcohol with minocycline or tigecycline in C57BL/6J mice (Agrawal et al., ; Syapin et al., ). Interestingly, while we did see sex differences in the antidrinking and antinociceptive actions of tigecycline in our companion studies (Bergeson et al., ; Syapin et al., ), we saw no sex differences or interactions in its ability to reduce alcohol‐withdrawal‐related seizure activity. Given that sex differences are known in general seizures (van Luijtelaar et al., ), coupled with the long‐known important role of sex as a factor in alcohol actions, including for withdrawal effects (Wiren et al., ), this was surprising.…”

Effective Reduction in High Ethanol Drinking by Semisynthetic Tetracycline Derivatives

“…Considering the strong microglial inhibition caused by minocycline (Garrido‐Mesa et al., ), tigecycline may share some of the actions and similarly have sexually distinct effects (Sorge et al., ). In fact, our companion paper’s results showed that tigecycline reduced neuroinflammatory pain in males, but not in females (Bergeson et al., ). Additionally, tetracyclines may affect a variety of nonmicrobial processes and it is possible some of the mechanisms show sex differences at higher doses, which lead to no further decrease in EtOH consumption in the female mice.…”

Repurposing Tigecycline for the Treatment of Alcohol Use Disorder

“…Interestingly, in rodent models of AUD, females display increased alcohol consumption relative to males, while the converse is observed in humans (Becker and Koob, ). Therefore, the results of Bergeson and colleagues () are particularly interesting, given that in rodent models, females are reported to be less affected by pain from alcohol withdrawal severity (Becker and Koob, ). One possible explanation for the paradoxical pro‐nociception reported for females in Bergeson and colleagues () may include the differential effects of tigecycline on pain responses in male versus female mice, which could involve cell‐specific immune‐related responses.…”

“…Therefore, the results of Bergeson and colleagues () are particularly interesting, given that in rodent models, females are reported to be less affected by pain from alcohol withdrawal severity (Becker and Koob, ). One possible explanation for the paradoxical pro‐nociception reported for females in Bergeson and colleagues () may include the differential effects of tigecycline on pain responses in male versus female mice, which could involve cell‐specific immune‐related responses. For example, sex‐dependent developmental expression of TLR in microglia (Lenz et al., ) in addition to differences in T‐cell activation in rodents has been reported (Sorge et al., ).…”

“…Paradoxically, uncontrolled chronic alcohol intake potentiates nociception in both males and females (Egli et al., ). Given the beneficial anti‐inflammatory effects of tetracyclines (Garrido‐Mesa et al., ), it is not surprising that Bergeson and colleagues () found tigecycline‐promoted antinociception in male C57BL/6J mice. What was surprising were the sex‐specific differences revealed by Bergeson and colleagues (Bergeson et al., ) in responses to pain, as tigecycline seemed to potentiate nociception in female C57BL/6J mice.…”