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

Abstract

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.

Spinal Nrf2 translocation may inhibit neuronal NF‐κB activation and alleviate allodynia in a rat model of bone cancer pain

“…Bone cancer pain (BCP) is a chronic pain and a severe complication of malignancy that is characterized by hyperalgesia and allodynia (Buga & Sarria, 2012;Wang et al, 2020). Previous studies have shown that BCP occurs in approximately 21% of the cancer patients who die of cancer, which severely affects the quality of life in these patients and increases the social burden (Kane et al, 2015;Turabi & Plunkett, 2012).…”

Predictive Value of the Phase Angle for Analgesic Efficacy in Lumbosacral Transforaminal Block

“…The mechanism of low back and leg pain involves mixed components of neuropathic and nociceptive mechanisms [ 25 ]. Spinal neuropathic pain is related to increased levels of inflammatory cytokines and disrupted and increased permeability of the blood–spinal barrier, originally composed of tight junctions of capillary endothelial cell surrounded by lamina [ 26 ]. Dysfunction and breakage of the blood–spinal cord barrier is observed in several neurodegenerative disorders, peripheral neural injury-induced inflammatory pain, and chemotherapy-induced neuropathic pain [ 26 , 27 ].…”

“…Spinal neuropathic pain is related to increased levels of inflammatory cytokines and disrupted and increased permeability of the blood–spinal barrier, originally composed of tight junctions of capillary endothelial cell surrounded by lamina [ 26 ]. Dysfunction and breakage of the blood–spinal cord barrier is observed in several neurodegenerative disorders, peripheral neural injury-induced inflammatory pain, and chemotherapy-induced neuropathic pain [ 26 , 27 ]. In a rat sciatic nerve model, recruitment of inflammatory materials outside the nerve led to damage of the epineurium and depletion of epineural adipocytes [ 21 , 28 ].…”

Sodium Tanshinone IIA Sulfonate Promotes Spinal Cord Injury Repair by Inhibiting BSCB Disruption In Vitro and In Vivo

“…Spinal cord injury (SCI) often leads to permanent loss of limb function defect due to disruption of the BSCB and the ensuing secondary injuries [35,36]. The BSCB is a semi-permeable interface of blood vessels that surrounds the spinal cord, and consists of the basement membrane, endothelial cells, pericytes, and astrocytes endplate foot processes [37]. The BSCB protects the spinal cord microenvironment from both endogenous and exogenous factors [38,39].…”