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A unique role for cAMP signaling in microglia during opioid tolerance and withdrawal

Neuropsychopharmacology volume 49, pages 331–332 (2024)Cite this article

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Upregulation of cyclic adenosine monophosphate (cAMP) signaling has been proposed as a general mechanism of opioid tolerance and withdrawal [1]. cAMP production via adenylyl cyclase is regulated by G protein-coupled receptors which ultimately increase (Gs) or decrease (Gi) neuronal excitability. Opioids activate Gi-coupled μ-opioid receptors (MORs) which inhibit cAMP signaling. As chronic opioid exposure induces tolerance, cAMP signaling and related genes are upregulated in MOR dense brain regions including the locus coeruleus and nucleus accumbens [1]. Upregulated genes include cAMP Response Element-Binding Protein (CREB) [1], Gs-coupled receptors (Adora2a, Drd1), and modulators of cAMP signaling (Arpp21, etc.) [2]. In neurons, these adaptations oppose opioid action (tolerance) and drive withdrawal symptoms upon abrupt discontinuation of MOR activation.

The upregulation of cAMP-related genes in response to naloxone antagonism of MORs suggests potent cAMP signaling occurs in microglia during withdrawal. One might think a burst of microglial cAMP would contribute to withdrawal symptoms as it does in neurons, but surprisingly the opposite appears true. The activation of hM4Di (Gi-coupled) DREADDs expressed in microglia inhibits adenylyl cyclase signaling while exacerbating signs of withdrawal (Fig. 1). This suggests that cAMP signaling in microglia may mitigate the acute behavioral effects of opioid withdrawal and that the increased translation of cAMP-related genes may produce compensatory effects in microglia that protect against withdrawal [4].

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Fig. 1: cAMP signaling in microglia may mitigate acute opioid withdrawal symptoms.

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Funding

Funding

This project was funded by UW NAPE Center pilot grant DA048736-03 (KRC), and NIDA grants K99DA052571 (KRC), DA052618 (JFN).

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Authors and Affiliations

  1. Department of Psychiatry & Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, 98105, USA

    Kevin R. Coffey & John F. Neumaier

  2. Mental Illness Research, Education and Clinical Center, Puget Sound VA Health Care System, 1660 S Columbian Way, Seattle, WA, 98108, USA

    John F. Neumaier

  3. Department of Pharmacology, University of Washington School of Medicine, Seattle, WA, 98105, USA

    John F. Neumaier

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  1. Kevin R. Coffey
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KC wrote and edited the manuscript and designed and edited the figure. John Neumaier wrote and edited the manuscript and designed and edited the figure.

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Correspondence to John F. Neumaier.

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Coffey, K.R., Neumaier, J.F. A unique role for cAMP signaling in microglia during opioid tolerance and withdrawal. Neuropsychopharmacol. 49, 331–332 (2024). https://doi.org/10.1038/s41386-023-01685-2

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