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Transient receptor potential (TRP) channels have emerged as potential sensors and transducers of inflammatory pain. The aims of this study were to investigate (1) the expression of TRP channels in intervertebral disc (IVD) cells in normal and inflammatory conditions and (2) the function of Transient receptor potential ankyrin 1 (TRPA1) and Transient receptor potential vanilloid 1 (TRPV1) in IVD inflammation and matrix homeostasis. RT-qPCR was used to analyze human fetal, healthy, and degenerated IVD tissues for the gene expression of TRPA1 and TRPV1. The primary IVD cell cultures were stimulated with either interleukin-1 beta (IL-1) or tumor necrosis factor alpha (TNF-) alone or in combination with TRPA1/V1 agonist allyl isothiocyanate (AITC, 3 and 10 mu M), followed by analysis of calcium flux and the expression of inflammation mediators (RT-qPCR/ELISA) and matrix constituents (RT-qPCR). The matrix structure and composition in caudal motion segments from TRPA1 and TRPV1 wild-type (WT) and knock-out (KO) mice was visualized by FAST staining. Gene expression of other TRP channels (A1, C1, C3, C6, V1, V2, V4, V6, M2, M7, M8) was also tested in cytokine-treated cells. TRPA1 was expressed in fetal IVD cells, 20% of degenerated IVDs, but not in healthy mature IVDs. TRPA1 expression was not detectable in untreated cells and it increased upon cytokine treatment, while TRPV1 was expressed and concomitantly reduced. In inflamed IVD cells, 10 mu M AITC activated calcium flux, induced gene expression of IL-8, and reduced disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and collagen 1A1, possibly via upregulated TRPA1. TRPA1 KO in mice was associated with signs of degeneration in the nucleus pulposus and the vertebral growth plate, whereas TRPV1 KO did not show profound changes. Cytokine treatment also affected the gene expression of TRPV2 (increase), TRPV4 (increase), and TRPC6 (decrease). TRPA1 might be expressed in developing IVD, downregulated during its maturation, and upregulated again in degenerative disc disease, participating in matrix homeostasis. However, follow-up studies with larger sample sizes are needed to fully elucidate the role of TRPA1 and other TRP channels in degenerative disc disease.
In animals and humans, behavior can be influenced by irrelevant stimuli, a phenomenon called Pavlovian-to-instrumental transfer (PIT). In subjects with substance use disorder, PIT is even enhanced with functional activation in the nucleus accumbens (NAcc) and amygdala. While we observed enhanced behavioral and neural PIT effects in alcohol-dependent subjects, we here aimed to determine whether behavioral PIT is enhanced in young men with high-risk compared to low-risk drinking and subsequently related functional activation in an a-priori region of interest encompassing the NAcc and amygdala and related to polygenic risk for alcohol consumption. A representative sample of 18-year old men (n = 1937) was contacted: 445 were screened, 209 assessed: resulting in 191 valid behavioral, 139 imaging and 157 genetic datasets. None of the subjects fulfilled criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders-IV-TextRevision (DSM-IV-TR). We measured how instrumental responding for rewards was influenced by background Pavlovian conditioned stimuli predicting action-independent rewards and losses. Behavioral PIT was enhanced in high-compared to low-risk drinkers (b = 0.09, SE = 0.03, z = 2.7, p < 0.009). Across all subjects, we observed PIT-related neural blood oxygen level-dependent (BOLD) signal in the right amygdala (t = 3.25, p(SVC) = 0.04, x = 26, y = -6, z = -12), but not in NAcc. The strength of the behavioral PIT effect was positively correlated with polygenic risk for alcohol consumption (r(s) = 0.17, p = 0.032). We conclude that behavioral PIT and polygenic risk for alcohol consumption might be a biomarker for a subclinical phenotype of risky alcohol consumption, even if no drug-related stimulus is present. The association between behavioral PIT effects and the amygdala might point to habitual processes related to out PIT task. In non-dependent young social drinkers, the amygdala rather than the NAcc is activated during PIT; possible different involvement in association with disease trajectory should be investigated in future studies.
Locally delivered anti-inflammatory compounds can restore the homeostasis of the degenerated intervertebral disc (IVD). With beneficial effects on IVD cells, epigallocatechin 3-gallate (EGCG) is a promising therapeutic candidate. However, EGCG is prone to rapid degradation and/or depletion. Therefore, the purpose of this study was to develop a method for controlled EGCG delivery in the degenerated IVD. Primary IVD cells were isolated from human donors undergoing IVD surgeries. EGCG was encapsulated into microparticles by electrospraying of glutaraldehyde-crosslinked gelatin. The resulting particles were characterized in terms of cytocompatibility and anti-inflammatory activity, and combined with a thermoresponsive carrier to produce an injectable EGCG delivery system. Subsequently, electrospraying was scaled up using the industrial NANOSPIDER (TM) technology. The produced EGCG microparticles reduced the expression of inflammatory (IL-6, IL-8, COX-2) and catabolic (MMP1, MMP3, MMP13) mediators in pro-inflammatory 3D cell cultures. Combining the EGCG microparticles with the carrier showed a trend towards modulating EGCG activity/release. Electrospray upscaling was achieved, leading to particles with homogenous spherical morphologies. In conclusion, electrospray-based encapsulation of EGCG resulted in cytocompatible microparticles that preserved the activity of EGCG and showed the potential to control EGCG release, thus favoring IVD health by downregulating local inflammation. Future studies will focus on further exploring the biological activity of the developed delivery system for potential clinical use.
Compulsive behaviors (e.g., addiction) can be viewed as an aberrant decision process where inflexible reactions automatically evoked by stimuli (habit) take control over decision making to the detriment of a more flexible (goal-oriented) behavioral learning system. These behaviors are thought to arise from learning algorithms known as "model-based" and "model-free" reinforcement learning. Gambling disorder, a form of addiction without the confound of neurotoxic effects of drugs, showed impaired goal-directed control but the way in which problem gamblers (PG) orchestrate model-based and model-free strategies has not been evaluated. Forty-nine PG and 33 healthy participants (CP) completed a two-step sequential choice task for which model-based and model-free learning have distinct and identifiable trial-by-trial learning signatures. The influence of common psychopathological comorbidities on those two forms of learning were investigated. PG showed impaired model-based learning, particularly after unrewarded outcomes. In addition, PG exhibited faster reaction times than CP following unrewarded decisions. Troubled mood, higher impulsivity (i.e., positive and negative urgency) and current and chronic stress reported via questionnaires did not account for those results. These findings demonstrate specific reinforcement learning and decision-making deficits in behavioral addiction that advances our understanding and may be important dimensions for designing effective interventions.