Sphingosine-1-phosphate receptor subtype 1 activation in the central nervous system contributes to morphine withdrawal in rodents

Opioid therapies for chronic pain are undermined by many adverse side effects that reduce their efficacy and lead to dependence, abuse, reduced quality of life, and even death. We have recently reported that sphingosine-1-phosphate (S1P) 1 receptor (S1PR1) antagonists block the development of morphine-induced hyperalgesia and analgesic tolerance. However, the impact of S1PR1 antagonists on other undesirable side effects of opioids, such as opioid-induced dependence, remains unknown. Here, we demonstrate that naloxone-precipitated morphine withdrawal in mice altered de novo sphingolipid metabolism in the dorsal horn of the spinal cord and increased S1P that accompanied the manifestation of several withdrawal behaviors. Blocking de novo sphingolipid metabolism with intrathecal administration of myriocin, an inhibitor of serine palmitoyltransferase, blocked naloxone-precipitated withdrawal. Noteworthy, we found that competitive (NIBR-15) and functional (FTY720) S1PR1 antagonists attenuated withdrawal behaviors in mice. Mechanistically, at the level of the spinal cord, naloxone-precipitated withdrawal was associated with increased glial activity and formation of the potent inflammatory/neuroexcitatory cytokine interleukin-1β (IL-1β); these events were attenuated by S1PR1 antagonists. These results provide the first molecular insight for the role of the S1P/S1PR1 axis during opioid withdrawal. Our data identify S1PR1 antagonists as potential therapeutics to mitigate opioid-induced dependence and support repurposing the S1PR1 functional antagonist FTY720, which is FDA-approved for multiple sclerosis, as an opioid adjunct.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:17

Enthalten in:

Journal of neuroinflammation - 17(2020), 1 vom: 22. Okt., Seite 314

Sprache:

Englisch

Beteiligte Personen:

Doyle, Timothy M [VerfasserIn]
Hutchinson, Mark R [VerfasserIn]
Braden, Kathryn [VerfasserIn]
Janes, Kali [VerfasserIn]
Staikopoulos, Vicky [VerfasserIn]
Chen, Zhoumou [VerfasserIn]
Neumann, William L [VerfasserIn]
Spiegel, Sarah [VerfasserIn]
Salvemini, Daniela [VerfasserIn]

Links:

Volltext

Themen:

36B82AMQ7N
76I7G6D29C
Analgesics, Opioid
Fingolimod Hydrochloride
G926EC510T
GFAP, CD11b, IL-1β
Journal Article
Morphine
Naloxone
Naloxone-precipitated withdrawal
Narcotic Antagonists
S1pr1 protein, mouse
Sphingosine-1-Phosphate Receptors
Sphingosine-1-phosphate
Sphingosine-1-phosphate receptor subtype 1

Anmerkungen:

Date Completed 19.08.2021

Date Revised 19.08.2021

published: Electronic

Citation Status MEDLINE

doi:

10.1186/s12974-020-01975-2

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM316615242