Latent Sensitization: A Model for Stress‐Sensitive Chronic Pain

Marvizón, Juan Carlos G.; Walwyn, Wendy; Minasyan, Ani; Chen, Wenling; Taylor, Bradley K.

doi:10.1002/0471142301.ns0950s71

Cited by 39 publications

(71 citation statements)

References 38 publications

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“…These findings indicate that the neurolide 2 treatment reverts spinal pharmacology in primed mice back to a state that is observed in naive mice, suggesting a reversal of the pathological plasticity state. A similar model, termed “latent sensitization,” has been used to demonstrate that dorsal horn μ-opioid, and perhaps other G-protein-coupled receptors, 33 acquire constitutive activity following peripheral inflammation. These constitutively active receptors then mask hyperalgesia that can be revealed with administration of a μ-opioid inverse agonist.…”

Section: Discussionmentioning

confidence: 99%

Neuroligin 2 regulates spinal GABAergic plasticity in hyperalgesic priming, a model of the transition from acute to chronic pain

Kim

Megat

Moy

et al. 2016

Pain

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Plasticity in inhibitory receptors, neurotransmission, and networks is an important mechanism for nociceptive signal amplification in the spinal dorsal horn. We studied potential changes in GABAergic pharmacology and its underlying mechanisms in hyperalgesic priming, a model of the transition from acute to chronic pain. We find that while GABAA agonists and positive allosteric modulators reduce mechanical hypersensitivity to an acute insult, they fail to do so during the maintenance phase of hyperalgesic priming. In contrast, GABAA antagonism promotes antinociception and a reduction in facial grimacing after the transition to a chronic pain state. During the maintenance phase of hyperalgesic priming, we observed increased neuroligin (nlgn) 2 expression in the spinal dorsal horn. This protein increase was associated with an increase in nlgn2A splice variant mRNA, which promotes inhibitory synaptogenesis. Disruption of nlgn2 function with the peptide inhibitor, neurolide 2, produced mechanical hypersensitivity in naive mice but reversed hyperalgesic priming in mice previously exposed to brain-derived neurotrophic factor. Neurolide 2 treatment also reverses the change in polarity in GABAergic pharmacology observed in the maintenance of hyperalgesic priming. We propose that increased nlgn2 expression is associated with hyperalgesic priming where it promotes dysregulation of inhibitory networks. Our observations reveal new mechanisms involved in the spinal maintenance of a pain plasticity and further suggest that disinhibitory mechanisms are central features of neuroplasticity in the spinal dorsal horn.

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Section: Discussionmentioning

confidence: 99%

Neuroligin 2 regulates spinal GABAergic plasticity in hyperalgesic priming, a model of the transition from acute to chronic pain

Kim

Megat

Moy

et al. 2016

Pain

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“…The chemicals used in this study were: PGE 2 (a hyperalgesic agent that sensitizes nociceptors directly), complete Freund’s adjuvant (CFA; [57]), DAMGO [[D-Ala 2 , N-Me-Phe 4 , Gly 5 -ol]-enkephalin acetate salt, a MOR agonist; [9]], naltrexone (NTX, a MOR antagonist; [57]), naloxone (a MOR antagonist), FAK inhibitor 14 (focal adhesion kinase inhibitor), U0126 (MAPK/ERK inhibitor), and SU 6656 [a Src family kinase inhibitor; [9; 10]], all from Sigma-Aldrich (St. Louis, MO, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Inflammation (e.g., induced by complete Freund’s adjuvant [CFA]) produces constitutive MOR activity that chronically suppressed nociceptive signaling in the spinal cord for months [22; 57]. Pharmacological blockade during the post-hyperalgesia state with MOR inverse agonists, such as naltrexone, reinstated central pain sensitization [22; 57], a phenomenon referred to as “latent pain sensitization” [12; 18] or “latent sensitization” [48; 57].…”

Section: Methodsmentioning

confidence: 99%

“…Latent sensitization is a model similar to type II priming and, was initially found to develop in the setting of opioid-induced hyperalgesia, triggered by the repeated administration of opiates like heroin, morphine [19; 47], fentanyl [12; 64; 65] and remifentanil [18]. Recently, it has been suggested that administration of complete Freund’s adjuvant (CFA) in the rat hindpaw also induces latent sensitization, since the CFA-induced peripheral inflammation causes an increase in the constitutive MOR activity in the spinal cord, as a consequence of the augmented release of endogenous opioids [22; 57]. Thus, in both models, DAMGO-induced type II priming [9] and CFA-induced latent sensitization [22; 57] share similar features, including production of hyperalgesia in response an opioid receptor antagonist and their long lasting permanence [3; 22; 57].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, it has been suggested that administration of complete Freund’s adjuvant (CFA) in the rat hindpaw also induces latent sensitization, since the CFA-induced peripheral inflammation causes an increase in the constitutive MOR activity in the spinal cord, as a consequence of the augmented release of endogenous opioids [22; 57]. Thus, in both models, DAMGO-induced type II priming [9] and CFA-induced latent sensitization [22; 57] share similar features, including production of hyperalgesia in response an opioid receptor antagonist and their long lasting permanence [3; 22; 57]. However, the mechanism responsible for the maintenance of these primed states is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Hyperalgesic priming (type II) induced by repeated opioid exposure: maintenance mechanisms

Araldi

Ferrari

Levine

2017

Pain

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We previously developed a model of opioid-induced neuroplasticity in the peripheral terminal of the nociceptor that could contribute to opioid-induced hyperalgesia, type II hyperalgesic priming. Repeated administration of mu-opioid receptor (MOR) agonists, such as DAMGO, at the peripheral terminal of the nociceptor, induces long-lasting plasticity expressed, prototypically as opioid-induced hyperalgesia and prolongation of prostaglandin-E2-induced hyperalgesia. In this study, we evaluated the mechanisms involved in the maintenance of type II priming. Opioid receptor antagonist, naloxone, induced hyperalgesia in DAMGO-primed paws. When repeatedly injected, naloxone induced hyperalgesia, and hyperalgesic priming, supporting the suggestion that maintenance of priming involves changes in mu-opioid receptor (MOR) signaling. However, the knockdown of MOR with oligodeoxynucleotide antisense did not reverse priming. Mitogen-activated protein kinase (MAPK) and focal adhesion kinase, which are involved in the Src signaling pathway, previously implicated in type II priming, also inhibited the expression, but not maintenance of priming. However, when Src and MAPK inhibitors were co-administered, type II priming was reversed, in male rats. A second model of priming, latent sensitization, induced by complete Freund’s adjuvant (CFA) was also reversed, in males. In females, the inhibitor combination was only able to inhibit the expression and maintenance of DAMGO-induced priming when knockdown of G-protein-coupled estrogen receptor 30 (GPR30) in the nociceptor was performed. These findings demonstrate that the maintenance of DAMGO-induced type II priming and latent sensitization is mediated by an interaction between, Src and MAP kinases, which in females is GPR30 dependent.

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An In Vivo Mouse Model for Chronic Inflammation–Induced Immune Suppression: A “Factory” for Myeloid‐Derived Suppressor Cells (MDSCs)

Ben‐Meir¹,

Twaik²,

Meirow³

et al. 2022

Current Protocols

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Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells known to play a role in perpetuating a wide range of pathologies, such as chronic infections, autoimmune diseases, and cancer. MDSCs were first identified in mice by the markers CD11b + Gr1 + , and later, based on their morphology, they were classified into two subsets: polymorphonuclear MDSCs, identified by the markers CD11b + Ly6G + Ly6C Low , and monocytic MDSCs, detected as being CD11b + Ly6G -Ly6C Hi . MDSCs are studied as immunosuppressive cells in various diseases characterized by chronic inflammation and are associated with disease causes/triggers such as pathogens, autoantigens, and cancer. Therefore, different diseases may diversely affect MDSC metabolism, migration, and differentiation, thus influencing the generated MDSC functional features and ensuing suppressive environment. In order to study MDSCs in a pathology-free environment, we established and calibrated a highly reproducible mouse model that results in the development of chronic inflammation, which is the major cause of MDSC accumulation and immune suppression. The model presented can be used to study MDSC phenotypes, functional diversity, and plasticity. It also permits study of MDSC migration from the bone marrow to peripheral lymphatic and non-lymphatic organs and MDSC crosstalk with extrinsic factors, both in vivo and ex vivo. Furthermore, this model can serve as a platform to assess the effects of anti-MDSC modalities.

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Latent Sensitization: A Model for Stress‐Sensitive Chronic Pain

Cited by 39 publications

References 38 publications

Neuroligin 2 regulates spinal GABAergic plasticity in hyperalgesic priming, a model of the transition from acute to chronic pain

Neuroligin 2 regulates spinal GABAergic plasticity in hyperalgesic priming, a model of the transition from acute to chronic pain

Hyperalgesic priming (type II) induced by repeated opioid exposure: maintenance mechanisms

An In Vivo Mouse Model for Chronic Inflammation–Induced Immune Suppression: A “Factory” for Myeloid‐Derived Suppressor Cells (MDSCs)

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