TY - JOUR
AU - Xu, Tao
AB - 

Background
Analgesic tolerance due to long-term use of morphine remains a challenge for pain management. Morphine acts on μ-opioid receptors and downstream of the phosphatidylinositol 3-kinase signaling pathway to activate the mammalian target of rapamycin (mTOR) pathway. Rheb is an important regulator of growth and cell-cycle progression in the central nervous system owing to its critical role in the activation of mTOR. The hypothesis was that signaling via the GTP-binding protein Rheb in the dorsal horn of the spinal cord is involved in morphine-induced tolerance.


Methods
Male and female wild-type C57BL/6J mice or transgenic mice (6 to 8 weeks old) were injected intrathecally with saline or morphine twice daily at 12-h intervals for 5 consecutive days to establish a tolerance model. Analgesia was assessed 60 min later using the tail-flick assay. After 5 days, the spine was harvested for Western blot or immunofluorescence analysis.


Results
Chronic morphine administration resulted in the upregulation of spinal Rheb by 4.27 ± 0.195-fold (P = 0.0036, n = 6), in turn activating mTOR by targeting rapamycin complex 1 (mTORC1). Genetic overexpression of Rheb impaired morphine analgesia, resulting in a tail-flick latency of 4.65 ± 1.10 s (P < 0.0001, n = 7) in Rheb knock-in mice compared to 10 s in control mice (10 ± 0 s). Additionally, Rheb overexpression in spinal excitatory neurons led to mTORC1 signaling overactivation. Genetic knockout of Rheb or inhibition of mTORC1 signaling by rapamycin potentiated morphine-induced tolerance (maximum possible effect, 52.60 ± 9.56% in the morphine + rapamycin group vs. 16.60 ± 8.54% in the morphine group; P < 0.0001). Moreover, activation of endogenous adenosine 5′-monophosphate-activated protein kinase inhibited Rheb upregulation and retarded the development of morphine-dependent tolerance (maximum possible effect, 39.51 ± 7.40% in morphine + metformin group vs. 15.58 ± 5.79% in morphine group; P < 0.0001).


Conclusions
This study suggests spinal Rheb as a key molecular factor for regulating mammalian target of rapamycin signaling.


Editor’s Perspective

What We Already Know about This Topic


Analgesic tolerance after chronic administration of morphine involves the activation of the mammalian target of rapamycin pathway in the spinal cord


Rheb is a GTP-binding protein that modulates mammalian target of rapamycin signaling and plays an important role in the pathogenesis of chronic pain


The role of the Rheb signaling pathway in morphine-induced tolerance remains unknown




What This Article Tells Us That Is New


In mice, repeated administration of morphine increased expression of Rheb, leading to activation of mammalian target of rapamycin signaling in the spinal cord


Genetic overexpression of Rheb impaired morphine analgesia, whereas the deletion of Rheb had opposite effects


These results suggest that the Rheb–mammalian target of rapamycin signaling pathway plays an important role in the development and maintenance of morphine-induced tolerance





TI - Small G-Protein Rheb Gates Mammalian Target of Rapamycin Signaling to Regulate Morphine Tolerance in Mice
JF - Anesthesiology
DO - 10.1097/aln.0000000000004885
DA - 2024-04-26
UR - https://www.deepdyve.com/lp/wolters-kluwer-health/small-g-protein-rheb-gates-mammalian-target-of-rapamycin-signaling-to-IXz76PpEsh
SP - 786
EP - 802
VL - 140
IS - 4
DP - DeepDyve
ER -