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RSK2 Signaling in Medial Habenula Contributes to Acute Morphine Analgesia
- Source :
- Neuropsychopharmacology. 37:1288-1296
- Publication Year :
- 2012
- Publisher :
- Springer Science and Business Media LLC, 2012.
-
Abstract
- It has been established that mu opioid receptors activate the ERK1/2 signaling cascade both in vitro and in vivo. The Ser/Thr kinase RSK2 is a direct downstream effector of ERK1/2 and has a role in cellular signaling, cell survival growth, and differentiation; however, its role in biological processes in vivo is less well known. Here we determined whether RSK2 contributes to mu-mediated signaling in vivo. Knockout mice for the rsk2 gene were tested for main morphine effects, including analgesia, tolerance to analgesia, locomotor activation, and sensitization to this effect, as well as morphine withdrawal. The deletion of RSK2 reduced acute morphine analgesia in the tail immersion test, indicating a role for this kinase in mu receptor-mediated nociceptive processing. All other morphine effects and adaptations to chronic morphine were unchanged. Because the mu opioid receptor and RSK2 both show high density in the habenula, we specifically downregulated RSK2 in this brain metastructure using an adeno-associated-virally mediated shRNA approach. Remarkably, morphine analgesia was significantly reduced, as observed in the total knockout animals. Together, these data indicate that RSK2 has a role in nociception, and strongly suggest that a mu opioid receptor–RSK2 signaling mechanism contributes to morphine analgesia at the level of habenula. This study opens novel perspectives for both our understanding of opioid analgesia, and the identification of signaling pathways operating in the habenular complex.
- Subjects :
- Nociception
Cell signaling
Narcotic Antagonists
Motor Activity
Pharmacology
Ribosomal Protein S6 Kinases, 90-kDa
Mice
Transduction, Genetic
Drug tolerance
medicine
Animals
RNA, Small Interfering
Pain Measurement
Mice, Knockout
Analysis of Variance
Habenula
Behavior, Animal
Morphine
Naloxone
business.industry
Drug Tolerance
Analgesics, Opioid
Mice, Inbred C57BL
Psychiatry and Mental health
Opioid
Knockout mouse
Original Article
Signal transduction
μ-opioid receptor
business
Morphine Dependence
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 1740634X and 0893133X
- Volume :
- 37
- Database :
- OpenAIRE
- Journal :
- Neuropsychopharmacology
- Accession number :
- edsair.doi.dedup.....5b43764b71ac71f66f796f4a6d6fc0d9