Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Sep 15:8:100052.
doi: 10.1016/j.ynpai.2020.100052. eCollection 2020 Aug-Dec.

Chronic inflammatory pain alters alcohol-regulated frontocortical signaling and associations between alcohol drinking and thermal sensitivity

M Adrienne McGinn  1 , Kimberly N Edwards  2   3 , Scott Edwards  2   3   4   5
Affiliations

Chronic inflammatory pain alters alcohol-regulated frontocortical signaling and associations between alcohol drinking and thermal sensitivity

M Adrienne McGinn et al. Neurobiol Pain. .

Abstract

Alcohol use disorder (AUD) is a chronic, relapsing psychiatric disorder that is characterized by the emergence of negative affective states. The transition from recreational, limited intake to uncontrolled, escalated intake is proposed to involve a transition from positive to negative reinforcement mechanisms for seeking alcohol. Past work has identified the emergence of significant hyperalgesia/allodynia in alcohol-dependent animals, which may serve as a key negative reinforcement mechanism. Chronic pain has been associated with enhanced extracellular signal-regulated kinase (ERK) activity in cortical and subcortical nociceptive areas. Additionally, both pain and AUD have been associated with increased activity of the glucocorticoid receptor (GR), a key mediator of stress responsiveness. The objectives of the current study were to first determine relationships between thermal nociceptive sensitivity and alcohol drinking in male Wistar rats. While inflammatory pain induced by complete Freund's adjuvant (CFA) administration did not modify escalation of home cage drinking in animals over four weeks, the relationship between drinking levels and hyperalgesia symptoms reversed between acute (1 week) and chronic (3-4 week) periods post-CFA administration, suggesting that either the motivational or analgesic effects of alcohol may be altered over the time course of chronic pain. We next examined ERK and GR phosphorylation in pain-related brain areas (including the central amygdala and prefrontal cortex subregions) in animals experiencing acute withdrawal from binge alcohol administration (2 g/kg, 6 h withdrawal) and CFA administration (four weeks) to model the neurobiological consequences of binge alcohol exposure in the context of pain. We observed a significant interaction between alcohol and pain state, whereby alcohol withdrawal increased ERK phosphorylation across all four frontocortical areas examined, although this effect was absent in animals experiencing chronic inflammatory pain. Alcohol withdrawal also increased GR phosphorylation across all four frontocortical areas, but these changes were not altered by CFA. Interestingly, we observed significant inter-brain regional correlations in GR phosphorylation between the insula and other regions investigated only in animals exposed to both alcohol and CFA, suggesting coordinated activity in insula circuitry and glucocorticoid signaling in this context. The results of these studies provide a greater understanding of the neurobiology of AUD and will contribute to the development of effective treatment strategies for comorbid AUD and pain.

Keywords: Alcohol; Central amygdala; ERK; Glucocorticoid receptor; Pain; Prefrontal cortex.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Chronic inflammatory pain, thermal hyperalgesia, and alcohol consumption and preference over time in a 2-bottle choice intermittent access drinking procedure. There were no significant differences between treatment groups in (A) alcohol consumption over 24 h, or (B) preference for alcohol over water. There was a significant escalation of both alcohol consumption (###p < 0.001 main effect of time) and preference (####p < 0.0001 main effect of time) over the four-week period. (C) CFA-treated male rats displayed cold hyperalgesia over four weeks post-CFA injection (####p < 0.0001 main effect of group). Data are represented as mean ± SEM. Control, white (n = 7); CFA-treated, red (n = 7). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 2
Fig. 2
Relationship between thermal hyperalgesia and alcohol consumption in animals with chronic inflammatory pain over four weeks. (A) Hindpaw-withdrawal latency negatively correlated with prior 24 h alcohol consumption 1 week post-CFA treatment (R = −0.7922, p = 0.034); (B) There was no correlation between hindpaw-withdrawal latency and prior 24-hour alcohol consumption 2 weeks post-CFA treatment (R = −0.1983, p = 0.670); (C) Hindpaw-withdrawal latency positively correlated with prior 24-hour alcohol consumption 3 weeks post-CFA treatment (R = 0.8184, p = 0.024); (D) Hindpaw-withdrawal latency positively correlated with prior 24-hour alcohol consumption 4 weeks post-CFA treatment (R = 0.7495, p = 0.052). Data were analyzed using linear regression. CFA-treated, red (n = 7). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3
Fig. 3
Study timeline and regional brain dissections for molecular experiments.
Fig. 4
Fig. 4
Interaction of chronic inflammatory pain and binge alcohol withdrawal on ERK phosphorylation. Binge alcohol exposure and withdrawal increased ERK phosphorylation in control but not CFA-treated rats in the (A) dorsomedial PFC, (B) ventromedial PFC, and (C) anterior cingulate cortex. (D) There was a significant interaction for CFA treatment and acute alcohol withdrawal on pERK in the insula, but no significant differences between groups. (E) pERK in the central amygdala was not significantly altered by CFA treatment or acute alcohol withdrawal. (F) Representative Western blots of pERK and total ERK in the anterior cingulate cortex. Data were analyzed using 2-way ANOVA and Tukey’s post hoc tests. Data are represented as mean ± SEM. Saline control + saline, solid white (n = 9); Saline control + acute alcohol WD, white striped (n = 11); CFA + saline, solid red (n = 9); CFA + acute alcohol WD, red striped (n = 9). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 5
Fig. 5
The interaction of chronic inflammatory pain and binge alcohol withdrawal on glucocorticoid receptor phosphorylation. Binge alcohol exposure and withdrawal increased GR phosphorylation (Ser232 in both control and CFA-treated animals in the (A) dorsomedial PFC, (B) ventromedial PFC, (C) anterior cingulate cortex, and (D) insula (##p < 0.01, ###p < 0.001 main effect of group). (E) In the CeA, there was no effect of CFA treatment or acute alcohol WD on GR Ser232 phosphorylation. (F) Representative Western blots of pGR and total GR in the ventromedial PFC. Data were analyzed using 2-way RM ANOVA and Sidak's multiple comparisons test (B) or 2-way ANOVA and Tukey’s post hoc tests (C-G). Data are represented as mean ± SEM. Saline control + saline, solid white (n = 9); Saline control + acute alcohol WD, white striped (n = 11); CFA + saline, solid red (n = 9); CFA + acute alcohol WD, red striped (n = 9). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 6
Fig. 6
Inter-brain regional correlations between the insular cortex and other nociceptive brain regions. Significant positive correlations are evident in GR phosphorylation levels between the insula and all other areas investigated (dmPFC, vmPFC, anterior cingulate cortex, and central amygdala) in animals exposed to both binge alcohol withdrawal and CFA (for each region/axis, individual data are presented as percentage of control animals). Within-subject data were analyzed using linear regression. CFA-treated, red (n = 9). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Alexander J.K., DeVries A.C., Kigerl K.A., Dahlman J.M., Popovich P.G. Stress exacerbates neuropathic pain via glucocorticoid and NMDA receptor activation. Brain Behav. Immun. 2009;23(6):851–860. doi: 10.1016/j.bbi.2009.04.001. - DOI - PMC - PubMed
    1. Apkarian A.V., Neugebauer V., Koob G., Edwards S., Levine J.D., Ferrari L., Regunathan S. Neural mechanisms of pain and alcohol dependence. Pharmacol. Biochem. Behav. 2013;112:34–41. doi: 10.1016/j.pbb.2013.09.008. - DOI - PMC - PubMed
    1. Arienzo D., Happer J.P., Molnar S.M., Alderson-Myers A., Marinkovic K. Binge drinking is associated with altered resting state functional connectivity of reward-salience and top down control networks. Brain Imag. Behav. 2019 doi: 10.1007/s11682-019-00107-6. - DOI - PMC - PubMed
    1. Avegno E.M., Lobell T.D., Itoga C.A., Baynes B.B., Whitaker A.M., Weera M.M., Gilpin N.W. Central amygdala circuits mediate hyperalgesia in alcohol-dependent rats. J. Neurosci. 2018;38(36):7761–7773. doi: 10.1523/JNEUROSCI.0483-18.2018. - DOI - PMC - PubMed
    1. Barthas F., Humo M., Gilsbach R., Waltisperger E., Karatas M., Leman S., Yalcin I. Cingulate overexpression of mitogen-activated protein kinase phosphatase-1 as a key factor for depression. Biol. Psychiatry. 2017;82(5):370–379. doi: 10.1016/j.biopsych.2017.01.019. - DOI - PubMed

LinkOut - more resources