Changes in vascular permeability in the spinal cord contribute to chemotherapy-induced neuropathic pain

Montague-Cardoso, Karli; Pitcher, Thomas; Chisolm, Kim; Salera, Giorgia; Lindström, Erik; Hewitt, Ellen; Solito, Egle; Malcangio, Marzia

doi:10.1016/j.bbi.2019.10.018

Cited by 27 publications

(30 citation statements)

References 31 publications

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“…Under physiological conditions, the BSCB represents a tight barrier between the blood and CNS. Disruption of the BSCB occurs under various pathological conditions, such as ALS, 24 spinal cord injury 25 and neuropathic pain, 10 leading to increased permeability and subsequent damage. As shown in our previous study, T cells infiltrated into the spinal cord during the maintenance of BCP.…”

Section: Discussionmentioning

confidence: 99%

“… 9 According to recent studies, prolonged BSCB dysfunction facilitates the infiltration of peripheral leukocytes into the spinal parenchyma to amplify nociceptive signaling in chemotherapy-induced neuropathic pain and peripheral neural injury-induced inflammatory pain. 10 11 Therefore, the present study aimed to determine whether the analgesic effect of the CB2R-selective agonist JWH015 on BCP was mediated by improving the damaged BSCB.…”

Section: Introductionmentioning

confidence: 97%

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Spinal cannabinoid receptor 2 activation reduces hypersensitivity associated with bone cancer pain and improves the integrity of the blood–spinal cord barrier

Wang

et al. 2020

Reg Anesth Pain Med

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BackgroundDisruption of the blood–spinal cord barrier (BSCB) can facilitate inflammation that results in pain hypersensitivity. Proinflammatory cytokines produced by activated microglia and astrocytes damage the BSCB. This study aims to explore whether the BSCB is damaged in the bone cancer pain (BCP) model and to investigate a potential role and mechanism of JWH015 ((2-methyl-1-propyl-1H-indol-3-yl)−1-naphthalenylmethanone), a selective cannabinoid receptor 2 (CB2R) agonist, in preserving the BSCB integrity in the BCP model.MethodsWe used a male mouse model of BCP. Pain hypersensitivity was measured over time. Evans blue dye extravasation, transmission electron microscopy and Western blotting were performed to investigate the permeability and structural integrity of the BSCB. Immunofluorescence staining and western blotting were used to investigate the effect of JWH015 on the activation of glial cells and the levels of proinflammatory cytokines.ResultsA single intrathecal injection of JWH015 ameliorated pain hypersensitivity, the BSCB disruption and microglia and astrocyte activation. Decreases in the expression of ZO-1 and claudin-5 were partially restored by JWH015. The levels of the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α and the enzyme MMP9 were reduced by JWH015. However, all effects were prevented by pretreatment with a CB2R-selective antagonist, AM630 ((6-iodo-2-methyl-1-(2-morpholinoethyl)−1H-indol-3-yl)(4-methoxyphenyl)methanone).ConclusionsJWH015 alleviates neuroinflammation and maintains the BSCB integrity and permeability in a mouse model of BCP, which is probably mediated by inhibiting glial cells activation. This study reveals the new analgesic mechanism of JWH015 on BCP and provides a perspective to explore novel drugs that target the BSCB to control BCP.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Spinal cannabinoid receptor 2 activation reduces hypersensitivity associated with bone cancer pain and improves the integrity of the blood–spinal cord barrier

Wang

et al. 2020

Reg Anesth Pain Med

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“…Specifically, recent evidence from a preclinical model of chemotherapy-induced neuropathic pain suggests that an increase in CatS in the spinal cord, which in this case is attributed to infiltrating monocytes, is not only observed during the induction of pain-like behaviour, but play an important mechanistic nociceptive role. Specifically, in the vincristine (VCR) model of neuropathic pain, in which allodynia is observed within 24 h of the first chemotherapy dose, oral administration of a centrally-penetrant CatS inhibitor significantly reduces the severity of VCR-induced allodynia in the first 24 h [ 34 ]. Importantly, oral administration of a CatS inhibitor that does not penetrate the CNS does not have an appreciable effect on VCR-induced allodynia [ 34 ], strongly suggesting that inhibition of CatS in the spinal cord specifically is required for an anti-nociceptive effect to be observed.…”

Section: Cats and Preclinical Chronic Painmentioning

confidence: 99%

“…Specifically, in the vincristine (VCR) model of neuropathic pain, in which allodynia is observed within 24 h of the first chemotherapy dose, oral administration of a centrally-penetrant CatS inhibitor significantly reduces the severity of VCR-induced allodynia in the first 24 h [ 34 ]. Importantly, oral administration of a CatS inhibitor that does not penetrate the CNS does not have an appreciable effect on VCR-induced allodynia [ 34 ], strongly suggesting that inhibition of CatS in the spinal cord specifically is required for an anti-nociceptive effect to be observed. In the case of the VCR model of neuropathic pain however, the source of elevated CatS in the spinal cord is unlikely to be microglia, as it has been previously established that microglia are not activated in this particular model [ 35 ].…”

Section: Cats and Preclinical Chronic Painmentioning

confidence: 99%

“…In the case of the VCR model of neuropathic pain however, the source of elevated CatS in the spinal cord is unlikely to be microglia, as it has been previously established that microglia are not activated in this particular model [ 35 ]. Instead, alterations in vascular permeability at the blood-spinal cord barrier enable CatS-expressing circulating monocytes to infiltrate into the spinal cord [ 34 ]. Taken together, these data suggest the role of CatS in the spinal cord in preclinical chronic pain varies depending on the initial injury as well as the source of CatS elevation.…”

Section: Cats and Preclinical Chronic Painmentioning

confidence: 99%

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Cathepsin S as a potential therapeutic target for chronic pain

Montague-Cardoso

Malcangio

2020

Medicine in Drug Discovery

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Chronic pain is a distressing yet poorly-treated condition that can arise as a result of diseases and injuries to the nervous system. The development of more efficacious therapies for chronic pain is essential and requires advances in our understanding of its underlying mechanisms. Clinical and preclinical evidence has demonstrated that immune responses play a crucial role in chronic pain. The lysosomal cysteine protease cathepsin S (CatS) plays a key role in such immune response. Here we discuss the preclinical evidence for the mechanistic importance of extracellular CatS in chronic pain focussing on studies utilising drugs and other pharmacological tools that target CatS activity. We also consider the use of CatS inhibitors as potential novel antihyperalgesics, highlighting that the route and timing of delivery would need to be tailored to the initial cause of pain in order to ensure the most effective use of such drugs.

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Selective blood-nerve barrier leakiness with claudin-1 and vessel-associated macrophage loss in diabetic polyneuropathy

et al. 2021

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Diabetic polyneuropathy (DPN) is the most common complication in diabetes and can be painful in up to 26% of all diabetic patients. Peripheral nerves are shielded by the blood-nerve barrier (BNB) consisting of the perineurium and endoneurial vessels. So far, there are conflicting results regarding the role and function of the BNB in the pathophysiology of DPN. In this study, we analyzed the spatiotemporal tight junction protein profile, barrier permeability, and vessel-associated macrophages in Wistar rats with streptozotocin-induced DPN. In these rats, mechanical hypersensitivity developed after 2 weeks and loss of motor function after 8 weeks, while the BNB and the blood-DRG barrier were leakier for small, but not for large molecules after 8 weeks only. The blood-spinal cord barrier remained sealed throughout the observation period. No gross changes in tight junction protein or cytokine expression were observed in all barriers to blood. However, expression of Cldn1 mRNA in perineurium was specifically downregulated in conjunction with weaker vessel-associated macrophage shielding of the BNB. Our results underline the role of specific tight junction proteins and BNB breakdown in DPN maintenance and differentiate DPN from traumatic nerve injury. Targeting claudins and sealing the BNB could stabilize pain and prevent further nerve damage. Key messages • In diabetic painful neuropathy in rats: • Blood nerve barrier and blood DRG barrier are leaky for micromolecules. • Perineurial Cldn1 sealing the blood nerve barrier is specifically downregulated. • Endoneurial vessel-associated macrophages are also decreased. • These changes occur after onset of hyperalgesia thereby maintaining rather than inducing pain. Graphical abstract

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Changes in vascular permeability in the spinal cord contribute to chemotherapy-induced neuropathic pain

Cited by 27 publications

References 31 publications

Spinal cannabinoid receptor 2 activation reduces hypersensitivity associated with bone cancer pain and improves the integrity of the blood–spinal cord barrier

Spinal cannabinoid receptor 2 activation reduces hypersensitivity associated with bone cancer pain and improves the integrity of the blood–spinal cord barrier

Cathepsin S as a potential therapeutic target for chronic pain

Selective blood-nerve barrier leakiness with claudin-1 and vessel-associated macrophage loss in diabetic polyneuropathy

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