Abstract
Opioid withdrawal involves the manifestation of motivational and somatic symptoms. However, the brain structures that are involved in the expression of different opioid withdrawal signs remain unclear. We induced opioid dependence by repeatedly injecting escalating heroin doses in male and female C57BL/6J mice. We assessed hyperalgesia during spontaneous heroin withdrawal and somatic signs of withdrawal that was precipitated by the preferential µ-opioid receptor antagonist naloxone. Heroin-treated mice exhibited significantly higher hyperalgesia and somatic signs than saline-treated mice. Following behavioral assessment, we measured regional changes in brain activity by automated the counting of c-Fos expression (a marker of cellular activity). Using Principal Component Analysis, we determined the association between behavior (hyperalgesia and somatic signs of withdrawal) and c-Fos expression in different brain regions. Hyperalgesia was associated with c-Fos expression in the lateral hypothalamus, central nucleus of the amygdala, ventral tegmental area, parabrachial nucleus, dorsal raphe, and locus coeruleus. Somatic withdrawal was associated with c-Fos expression in the paraventricular nucleus of the thalamus, lateral habenula, dorsal raphe, and locus coeruleus. Thus, hyperalgesia and somatic withdrawal signs were each associated with c-Fos expression in unique sets of brain areas. The expression of c-Fos in the dorsal raphe and locus coeruleus was associated with both hyperalgesia and somatic withdrawal. Understanding common neurobiological mechanisms of acute and protracted opioid withdrawal may help identify new targets for treating this salient aspect of opioid use disorder.
SIGNIFICANCE STATEMENT
The public impact of the opioid crisis has prompted an effort to understand the neurobiological mechanisms of opioid use disorder (OUD). The need to avoid withdrawal symptoms is hypothesized to drive compulsive drug-taking and -seeking in OUD. Thus, understanding the mechanisms of acute and protracted opioid withdrawal may help identify new targets for treating this salient aspect of OUD. We reported brain structures that are associated with the expression of hyperalgesia and somatic signs of opioid withdrawal in male and female heroin-dependent mice. Hyperalgesia during spontaneous opioid withdrawal and somatic withdrawal resulted in c-Fos expression in autonomic and limbic brain regions. The expression of c-Fos in the dorsal raphe and locus coeruleus were associated with both hyperalgesia and somatic withdrawal.
Footnotes
No conflict of interest
This work was funded by the National Institute on Drug Abuse Intramural Research Program.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
