Development of opioid-induced hyperalgesia depends on reactive astrocytes controlled by Wnt5a signaling

Liu, Xin; Bae, Chilman; Liu, Bolong; Zhang, Yongmei; Zhou, Xiangfu; Zhang, Donghang; Zhou, Cheng; DiBua, Adriana; Schutz, Livia; Kaczocha, Martin; Puopolo, Michelino; Yamaguchi, Terry P.; Chung, Jin Mo; Tang, Shuang

doi:10.1038/s41380-022-01815-0

Cited by 14 publications

(13 citation statements)

References 76 publications

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“…Repeated morphine exposure is associated with a sex-specific increase in GFAP labelling in some brain regions in rats, 4 but an increase in spinal GFAP mRNA expression in both male and female mice. 29 Crucially, astrocyte ablation impaired the induction and maintenance of opioid-induced hyperalgesia in this latter study, highlighting the critical role of astrogliosis in induction of pain states. Our data further support a role of spinal astrocytes in the exacerbation of OA-like pain behavior following sustained exposure to morphine.…”

Section: Discussionmentioning

confidence: 59%

Sustained morphine exposure alters spinal NMDA receptor and astrocyte expression and exacerbates chronic pain behavior in female rats

Gonçalves,

Woodhams,

et al. 2024

PR9

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Introduction: Sustained opioid use has long-term negative impacts on future pain experience, particularly in women. This study aimed to investigate the underlying spinal neurobiology of this clinical observation in an experimental model of joint pain. Objectives: In this study, we tested the hypothesis that sustained opioid treatment exacerbates chronic pain responses and alters spinal cord dorsal horn astrogliosis and the expression of GluN2B-containing N-methyl-d-aspartate receptors in female rats. Methods: Subcutaneous morphine (3 mg/kg) or saline was administered twice daily for 1 week before inducing a model of joint knee pain (intra-articular injection of 2 mg of monosodium iodoacetate [MIA]) in adult female Sprague-Dawley rats, with pain-free controls receiving 50 µL of saline. Pain behavior (weight-bearing and mechanical paw withdrawal thresholds) was measured at baseline and at intervals thereafter. Twice-daily morphine/saline treatment was continued for up to 3 weeks after intra-articular injections, and spinal cord tissue was collected for Western blot analyses. Results: Area under the curve analysis of weight-bearing asymmetry confirmed a significant exacerbation of pain behavior in the morphine/MIA group, compared with the saline/MIA group (F(3,18) = 46.3, P < 0.0001), despite comparable joint damage in both groups. Sustained morphine treatment was associated with significant elevations in dorsal horn expression of astrocytic glial fibrillary acidic protein (27 ± 5% increase) and neuronal GluN2B (80 ± 30% increase), but not microglial IBA1, irrespective of the model of joint pain. Conclusion: These data suggest that sustained morphine treatment in female rats drives spinal cord plasticity, including spinal astrogliosis and the expression of GluN2B-containing N-methyl-d-aspartate receptors, priming the dorsal horn to incoming sensory inputs and producing exacerbated pain responses.

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Section: Discussionmentioning

confidence: 59%

Sustained morphine exposure alters spinal NMDA receptor and astrocyte expression and exacerbates chronic pain behavior in female rats

Gonçalves,

Woodhams,

et al. 2024

PR9

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“…Glial cells include oligodendrocytes, astrocytes, and microglia. Their contribution to the pathogenesis of pain induction and maintenance has been identified [ 48 , 49 , 50 , 51 , 52 ].…”

Section: Glial Cells In Pain Neural Circuitsmentioning

confidence: 99%

“…Robust astrogliosis (indicated by increased GFAP expression) has been observed in various animal pain models, including neuropathic pain, spinal cord injury pain, inflammatory pain and HIV-associated pain [ 77 , 78 , 79 , 80 , 81 , 82 ]. Ablation of reactive astrocytes, inhibition of the spinal astrogliosis, or spinal knockdown of GFAP expression reduces pain development in animal models [ 51 , 52 , 83 , 84 ]. Astrogliosis in the SDH of HIV patients is specifically associated with the development of neuropathic pain, suggesting a pathogenic contribution of astrocytes to pain development in humans [ 85 ].…”

Section: Glial Cells In Pain Neural Circuitsmentioning

confidence: 99%

“…It is well known that the overall excitability of neuronal networks in SDH is enhanced in pathologic pain, but the detailed circuitry alteration remains incompletely understood. Recently, it has been demonstrated that pathological pain is associated with not only an increased excitatory input onto excitatory neurons but also a decreased excitatory input onto inhibitory neurons, a process named NCP [ 51 , 52 ]. These polarizations are expected to drive hyperactivation of the nociceptive system and thus result in pathological pain ( Figure 5 ).…”

Section: Neural Circuit Polarization (Ncp): a Novel Form Of Neural Ci...mentioning

confidence: 99%

“…In addition to HIV-induced chronic pain, astrogliosis is also observed in opioid-induced hyperalgesia (OIH), and it is shown to be important in the development of NCP in this pain model. Namely, the selective block of astrogliosis effectively blocks OIH and NCP [ 52 ]. These data suggest that the NCP observed in chronic pain is dependent on astrogliosis, and it is presumably a general mechanism underlying wide-ranging pain models.…”

Section: Neural Circuit Polarization (Ncp): a Novel Form Of Neural Ci...mentioning

confidence: 99%

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Neural Circuitry Polarization in the Spinal Dorsal Horn (SDH): A Novel Form of Dysregulated Circuitry Plasticity during Pain Pathogenesis

Chen,

Tang

2024

Cells

Self Cite

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Pathological pain emerges from nociceptive system dysfunction, resulting in heightened pain circuit activity. Various forms of circuitry plasticity, such as central sensitization, synaptic plasticity, homeostatic plasticity, and excitation/inhibition balance, contribute to the malfunction of neural circuits during pain pathogenesis. Recently, a new form of plasticity in the spinal dorsal horn (SDH), named neural circuit polarization (NCP), was discovered in pain models induced by HIV-1 gp120 and chronic morphine administration. NCP manifests as an increase in excitatory postsynaptic currents (EPSCs) in excitatory neurons and a decrease in EPSCs in inhibitory neurons, presumably facilitating hyperactivation of pain circuits. The expression of NCP is associated with astrogliosis. Ablation of reactive astrocytes or suppression of astrogliosis blocks NCP and, concomitantly, the development of gp120- or morphine-induced pain. In this review, we aim to compare and integrate NCP with other forms of plasticity in pain circuits to improve the understanding of the pathogenic contribution of NCP and its cooperation with other forms of circuitry plasticity during the development of pathological pain.

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Modulation of the central nervous system immune response and neuroinflammation via Wnt signaling in health and neurodegenerative diseases

Fang

2024

Ibrain

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The immune response in the central nervous system (CNS) is a highly specialized and tightly regulated process essential for maintaining neural health and protecting against pathogens and injuries. The primary immune cells within the CNS include microglia, astrocytes, T cells, and B cells. They work together, continuously monitor the CNS environment for signs of infection, injury, or disease, and respond by phagocytosing debris, releasing cytokines, and recruiting other immune cells. In addition to providing neuroprotection, these immune responses must be carefully balanced to prevent excessive inflammation that can lead to neuronal damage and contribute to neurodegenerative diseases. Dysregulated immune responses in the CNS are implicated in various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Wnt signaling is a crucial pathway in the CNS that regulates various cellular processes critical for brain development, function, and maintenance. Despite enhancing immune responses in the health CNS, dysregulated Wnt signaling exacerbates neuroinflammation in the neurodegenerative brains. This review summarized the role of Wnt signaling in regulating immune response under different conditions. We then examined the role of immune response in healthy brains and during the development of neurodegenerative diseases. We also discussed therapeutic intervention in various neurodegenerative diseases through the modulation of the Wnt signaling pathway and neuroinflammation and highlighted challenges and limitations in current clinical trials.

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Development of opioid-induced hyperalgesia depends on reactive astrocytes controlled by Wnt5a signaling

Cited by 14 publications

References 76 publications

Sustained morphine exposure alters spinal NMDA receptor and astrocyte expression and exacerbates chronic pain behavior in female rats

Sustained morphine exposure alters spinal NMDA receptor and astrocyte expression and exacerbates chronic pain behavior in female rats

Neural Circuitry Polarization in the Spinal Dorsal Horn (SDH): A Novel Form of Dysregulated Circuitry Plasticity during Pain Pathogenesis

Modulation of the central nervous system immune response and neuroinflammation via Wnt signaling in health and neurodegenerative diseases

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