Astroglial Knockout of Glucocorticoid Receptor Attenuates Morphine Withdrawal Symptoms, but Not Antinociception and Tolerance in Mice

Abstract

The development of tolerance and drug dependence limit the clinical application of opioids for the treatment of severe pain. Glucocorticoid receptors (GRs) are among molecular substrates involved in these processes. Most studies focus on the role of neuronal GR, while the involvement of GR on glial cells is not fully understood. To address this issue, we used a transgenic model of conditional GR knockout mice, targeted to connexin 30-expressing astrocytes, treated with repeated doses of morphine. We observed no difference between control mice and astrocytic GR knockouts in the development of antinociceptive tolerance. Nevertheless, when animals were subjected to precipitated withdrawal, knockouts presented some attenuated symptoms, including jumping. Taken together, our data suggest that hippocampal and spinal astrocytic GRs appear to be involved in opioid withdrawal, and drugs targeting the GR may relieve some symptoms of morphine withdrawal without influencing its antinociceptive properties.

Delta Opioid Receptor in Astrocytes Contributes to Neuropathic Cold Pain and Analgesic Tolerance in Female Mice

“…Among the Gfap-Cre lines, the Tg(GFAP-cre)8Gtm line used in the present study was frequently employed and has been referenced in more than 40 publications, a part of which demonstrated the astrocytes specificity, see Chhatbar et al ( 2018 ) for example. Other astrocyte deleter lines were used to inactivate genes in astrocytes, including the tamoxifen-inducible Cx30-ERT2 line (Tertil et al, 2021 ). However, tamoxifen was shown to induce cellular stress in the nervous system.…”

“…Littermates were randomly assigned to experimental groups. The number of animals per group was designated in accordance with previous similar studies (Gaveriaux-Ruff et al, 2011 ; Martínez-Navarro et al, 2020 ; Tertil et al, 2021 ). The numbers of DOR-flox and GFAP-DOR-KO males and females of each genotype for each experiment were as follows: for assessment of mechanical sensitivity and neuropathy-induced allodynia, DOR-flox, n = 16 males, n = 16 females; GFAP-DOR-KO, n = 12 males, n = 11 females; for evaluation of SNC80-induced analgesia and analgesic tolerance, DOR-flox, n = 13 males, n = 10 females; GFAP-DOR-KO, n = 11 males, n = 7 females; for assessment of cold sensitivity and neuropathy-induced allodynia, DOR-flox, n = 14 males, n = 16 females; GFAP-DOR-KO, n = 14 males, n = 10 females.…”