Early single Aspirin-triggered Lipoxin blocked morphine anti-nociception tolerance through inhibiting NALP1 inflammasome: Involvement of PI3k/Akt signaling pathway

Tian, Yu; Liu, Ming; Mao-Ying, Qi-Liang; Liu, Huan; Wang, Zhifu; Zhang, Mengting; Wang, Jun; Li, Qian; Liu, Shenbin; Mi, Wen-Li; Ma, Hong-Jian; Wang, Yan-Qing

doi:10.1016/j.bbi.2015.06.016

Cited by 26 publications

(18 citation statements)

References 66 publications

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“…11 These parallel findings on the expression and function changes of miR-219 in the context of different types of pain could be viewed as one of the shared mechanisms between morphine tolerance and inflammatory/neuropathic pain, as a long-held view. 46,47 Interestingly, similar to our previous findings that the spinal expression of miR-219 was downregulated in chronic CFA pain models rather than acute formalin pain model, we did not observe any expression change of miR-219 in the DRG following acute morphine tolerance establishment. These findings partially reveal that there might exist inconsistent mechanisms between chronic morphine tolerance and acute morphine tolerance.…”

Section: Mir-219 In Primary Afferent Neurons Evokes Pain Sensitivity supporting

confidence: 89%

Downregulation of miR-219 enhances brain-derived neurotrophic factor production in mouse dorsal root ganglia to mediate morphine analgesic tolerance by upregulating CaMKIIγ

Cao

Zhang

et al. 2016

Mol Pain

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BackgroundIncreasing evidence suggests that microRNAs are functionally involved in the initiation and maintenance of pain hypersensitivity, including chronic morphine analgesic tolerance, through the posttranscriptional regulation of pain-related genes. We have previously demonstrated that miR-219 regulates inflammatory pain in the spinal cord by targeting calcium/calmodulin-dependent protein kinase II gamma (CaMKIIγ). However, whether miR-219 regulates CaMKIIγ expression in the dorsal root ganglia to mediate morphine tolerance remains unclear.ResultsMiR-219 expression was downregulated and CaMKIIγ expression was upregulated in mouse dorsal root ganglia following chronic morphine treatment. The changes in miR-219 and CaMKIIγ expression closely correlated with the development of morphine tolerance, which was measured using the reduction of percentage of maximum potential efficiency to thermal stimuli. Morphine tolerance was markedly delayed by upregulating miR-219 expression using miR-219 mimics or downregulating CaMKIIγ expression using CaMKIIγ small interfering RNA. The protein and mRNA expression of brain-derived neurotrophic factor were also induced in dorsal root ganglia by prolonged morphine exposure in a time-dependent manner, which were transcriptionally regulated by miR-219 and CaMKIIγ. Scavenging brain-derived neurotrophic factor via tyrosine receptor kinase B-Fc partially attenuated morphine tolerance. Moreover, functional inhibition of miR-219 via miR-219-sponge in naive mice elicited thermal hyperalgesia and spinal neuronal sensitization, which were both suppressed by CaMKIIγ small interfering RNA or tyrosine receptor kinase B-Fc.ConclusionsThese results demonstrate that miR-219 contributes to the development of chronic tolerance to morphine analgesia in mouse dorsal root ganglia by targeting CaMKIIγ and enhancing CaMKIIγ-dependent brain-derived neurotrophic factor expression.

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Section: Mir-219 In Primary Afferent Neurons Evokes Pain Sensitivity supporting

confidence: 89%

Downregulation of miR-219 enhances brain-derived neurotrophic factor production in mouse dorsal root ganglia to mediate morphine analgesic tolerance by upregulating CaMKIIγ

Cao

Zhang

et al. 2016

Mol Pain

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“…Furthermore, MOR was involved in spinal D2DR blockade-induced inhibition of PI3K/Akt-MAPK signaling. MOR-triggered activation of PI3K/Akt is involved in the development of morphine tolerance, 37 , 52 and our results showed that MOR-triggered activation of PI3K/Akt further activated MAPK to promote the development of morphine tolerance. Blockade of spinal D2DR inhibited MOR-triggered activation of the PI3K/Akt-MAPK signaling pathway, which provided a new target for the prevention or reduction of morphine tolerance.…”

Section: Discussionsupporting

confidence: 57%

“… 50 D2DR stimulates the formation of a protein complex composed of β-arrestin2, PP2A, and Akt to activate Akt-medicated signaling. 51 The activation of PI3K/Akt signaling promotes the development of morphine tolerance, 37 , 52 but researchers have not determined whether the PI3K/Akt signaling pathway is involved in morphine tolerance. The MAPK family, which includes extracellular signal-regulated protein kinase 1/2 (ERK1/2), p38 and c-Jun N-terminal kinase (JNK), is also involved in morphine tolerance.…”

Section: Discussionmentioning

confidence: 99%

Selective blockade of spinal D2DR by levo-corydalmine attenuates morphine tolerance via suppressing PI3K/Akt-MAPK signaling in a MOR-dependent manner

et al. 2018

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Morphine tolerance remains a challenge in the management of chronic pain in the clinic. As shown in our previous study, the dopamine D2 receptor (D2DR) expressed in spinal cord neurons might be involved in morphine tolerance, but the underlying mechanisms remain to be elucidated. In the present study, selective spinal D2DR blockade attenuated morphine tolerance in mice by inhibiting phosphatidylinositol 3 kinase (PI3K)/serine–threonine kinase (Akt)-mitogen activated protein kinase (MAPK) signaling in a μ opioid receptor (MOR)-dependent manner. Levo-corydalmine (l-CDL), which exhibited micromolar affinity for D2DR in D2/CHO-K1 cell lines in this report and effectively alleviated bone cancer pain in our previous study, attenuated morphine tolerance in rats with chronic bone cancer pain at nonanalgesic doses. Furthermore, the intrathecal administration of l-CDL obviously attenuated morphine tolerance, and the effect was reversed by a D2DR agonist in mice. Spinal D2DR inhibition and l-CDL also inhibited tolerance induced by the MOR agonist DAMGO. l-CDL and a D2DR small interfering RNA (siRNA) decreased the increase in levels of phosphorylated Akt and MAPK in the spinal cord; these changes were abolished by a PI3K inhibitor. In addition, the activated Akt and MAPK proteins in mice exhibiting morphine tolerance were inhibited by a MOR antagonist. Intrathecal administration of a PI3K inhibitor also attenuated DAMGO-induced tolerance. Based on these results, l-CDL antagonized spinal D2DR to attenuate morphine tolerance by inhibiting PI3K/Akt-dependent MAPK phosphorylation through MOR. These findings provide insights into a more versatile treatment for morphine tolerance.

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“…In a chronic morphine tolerance rat model, it was observed that Akt phosphorylation, cleaved Caspase-1dependent NALP1 inflammasome activation and IL-1β maturation in spinal cord neurons were significantly enhanced by morphine. This revealed the role of μ-opioid/PI3K-Akt signaling/NALP1 inflammasome cascade in the development of morphine tolerance, and how treatment with LY294002 significantly reduced Caspase-1 cleavage, NALP1 inflammasome activation and attenuated morphine tolerance [133]. It is well known that repeated and long-term exposure to opioids causes opioid receptor-mediated adaptive changes within the nervous system, including desensitization, internalization, downregulation, and phosphorylation of opioid receptors [134] or heterodimerization with other receptors [135].…”

Section: Pi3k/akt Pathway and Opioid Tolerance And Hyperalgesiamentioning

confidence: 94%

PI3K/Akt Pathway: A Potential Therapeutic Target for Chronic Pain

Chen

Zhou

Liu

et al. 2017

CPD

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Chronic pain is among the most disabling and costly disorders, with prevalence ranging from 10% to 55%. However, current therapeutic strategies for chronic pain are unsatisfactory due to our poor understanding of its mechanisms. Thus, novel therapeutic targets need to be found in order to improve these patients' quality of life. PI3K and its downstream Akt are widely expressed in the spinal cord, particularly in the laminae I-IV of the dorsal horn, where nociceptive C and Aδ fibers of primary afferents principally terminate. Recent studies have demonstrated their critical roles in the development and maintenance of chronic pain. In this review, we summarized the roles and mechanisms of PI3K/Akt pathway in the progression of chronic pain through sciatic nerve injury, diabetic neuropathy, spinal cord injury, bone cancer, opioid tolerance, or opioid-induced hyperalgesia.

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Early single Aspirin-triggered Lipoxin blocked morphine anti-nociception tolerance through inhibiting NALP1 inflammasome: Involvement of PI3k/Akt signaling pathway

Cited by 26 publications

References 66 publications

Downregulation of miR-219 enhances brain-derived neurotrophic factor production in mouse dorsal root ganglia to mediate morphine analgesic tolerance by upregulating CaMKIIγ

Downregulation of miR-219 enhances brain-derived neurotrophic factor production in mouse dorsal root ganglia to mediate morphine analgesic tolerance by upregulating CaMKIIγ

Selective blockade of spinal D2DR by levo-corydalmine attenuates morphine tolerance via suppressing PI3K/Akt-MAPK signaling in a MOR-dependent manner

PI3K/Akt Pathway: A Potential Therapeutic Target for Chronic Pain

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