Browse by Audience
The actions of caffeine as an antagonist of adenosine receptors have been extensively studied, and there is no doubt that both daily and sporadic dietary consumption of caffeine has substantial biological effects on the nervous system. Caffeine influences headaches, the migraine syndrome in particular, but how is unclear. This is a narrative review based on selected articles from an extensive literature search. The aim of this study is to elucidate and discuss how caffeine may affect the migraine syndrome and discuss the potential pathophysiological pathways involved. Whether caffeine has any significant analgesic and/or prophylactic effect in migraine remains elusive. Neither is it clear whether caffeine withdrawal is an important trigger for migraine. However, withdrawal after chronic exposure of caffeine may cause migraine-like headache and a syndrome similar to that experienced in the prodromal phase of migraine. Sensory hypersensitivity however, does not seem to be a part of the caffeine withdrawal syndrome. Whether it is among migraineurs is unknown. From a modern viewpoint, the traditional vascular explanation of the withdrawal headache is too simplistic and partly not conceivable. Peripheral mechanisms can hardly explain prodromal symptoms and non-headache withdrawal symptoms. Several lines of evidence point at the hypothalamus as a locus where pivotal actions take place. In general, chronic consumption of caffeine seems to increase the burden of migraine, but a protective effect as an acute treatment or in severely affected patients cannot be excluded. Future clinical trials should explore the relationship between caffeine withdrawal and migraine, and investigate the effects of long-term elimination.
Learn More >Although critical for informed consent, side effect warnings can contribute directly to poorer patient outcomes because they often induce negative expectations that trigger nocebo side effects. Communication strategies that reduce the development of nocebo side effects whilst maintaining informed consent are therefore of considerable interest. We reviewed theoretical and empirical evidence for the use of framing strategies to achieve this. Framing refers to the way in which information about the likelihood or significance of side effects is presented (e.g., negative frame: 30% experience headache vs. positive frame: 70% will experience headache), with the rationale that positively framing such information could diminish nocebo side effects. Relatively few empirical studies ( = 6) have tested whether framing strategies can reduce nocebo side effects. Of these, four used attribute framing and two message framing. All but one of the studies found a significant framing effect on at least one aspect of side effects (e.g., experience, attribution, threat), suggesting that framing is a promising strategy for reducing nocebo effects. However, our review also revealed some important open questions regarding these types of framing effects, including, the best method of communicating side effects (written, oral, pictorial), optimal statistical presentation (e.g., frequencies vs. percentages), whether framing affects perceived absolute risk of side effects, and what psychological mechanisms underlie framing effects. Future research that addresses these open questions will be vital for understanding the circumstances in which framing are most likely to be effective.
Learn More >Bladder pain is frequently associated with bladder inflammation, as in conditions like interstitial cystitis (IC), for which current analgesic therapies have limited efficacy. The antinociceptive effect of alpha-2-delta (αδ) ligands on inflammation-associated visceral pain like that experienced in cystitis has been poorly investigated. To investigate the effect of pregabalin (PGB), an αδ ligand, we evaluated its impact on mechanical hyperalgesia in a mouse model of cystitis induced by cyclophosphamide (CYP). We further studied its effect on inflammation and NF-kB pathway activation. Acute cystitis was induced by intraperitoneal injection of 150 mg kg of CYP in C57Bl/6J male mice. PGB was subcutaneously injected (30 mg kg) 3 h after CYP injection. The effect of PGB on CYP-induced mechanical referred hyperalgesia (abdominal Von Frey test), inflammation (organ weight, cytokine production, αδ subunit level, NF-kB pathway activation) were assessed 1 h after its injection. In parallel, its effect on cytokine production, αδ subunit level and NF-kB pathway activation was assessed on peritoneal exudate cells (PECs) stimulated with LPS. PGB treatment decreased mechanical referred hyperalgesia. Interestingly, it had an anti-inflammatory effect in the cystitis model by reducing pro-inflammatory cytokine production. PGB also inhibited NF-kB pathway activation in the cystitis model and in macrophages stimulated with LPS, in which it blocked the increase in intracellular calcium. This study shows the efficacy of PGB in hypersensitivity and inflammation associated with cystitis. It is therefore of great interest in assessing the benefit of αδ ligands in patients suffering from cystitis.
Learn More >Estrogen status is a significant risk factor in the development of temporomandibular joint disorders (TMD). Classically, estrogen status is thought to derive mainly from ovarian sources; however, it is well known that estradiol (E2) also is synthesized by neurons in the brain. This study tested the hypothesis that E2 is produced by neurons in trigeminal subnucleus caudalis (Vc), the principal site of termination for sensory afferents that supply the temporomandibular joint (TMJ), to modify evoked responses in a model of TMJ nociception in male and female rats. Intra-TMJ injection of the small fiber excitant, allyl isothiocyanate (AIC), increased the levels of E2 collected from microdialysis probes sites at Vc of ovariectomized (OvX) female rats, ipsilateral to the stimulus, whereas males displayed no change. Dialysate levels of E2 collected from probe sites in the contralateral Vc or cerebellum in OvX rats were not affected by TMJ stimulation. Reverse dialysis of anastrozole, an aromatase (ARO) inhibitor, via the probe reduced perfusate levels of E2 in Vc. Systemic administration of letrozole, a non-steroid ARO inhibitor, for 4 days prevented TMJ-evoked increases in masseter muscle electromyography (MMemg) activity. ARO-positive neurons were distributed mainly in superficial laminae (I-III) at Vc and cell counts revealed no significant difference between OvX and male rats. Intra-TMJ injection of AIC revealed similar numbers of ARO/Fos dual-labeled neurons in OvX and male rats. By contrast, the percentage of ARO neurons co-labeled for glutamic acid decarboxylase (GAD), the biosynthetic enzyme for GABA, was greater in OvX (35%) than male rats (14%). Few ARO-positive neurons were co-labeled for estrogen receptor alpha. These data indicate that E2 is secreted continuously by Vc neurons and that acute stimulation of TMJ nociceptors evokes further secretion in a sex-dependent manner. Reduced TMJ-evoked MMemg activity after ARO inhibition suggests that locally produced E2 by Vc neurons acts via paracrine mechanisms to modify TMJ nociception in female rats.
Learn More >Our previous study suggested that HBO treatment attenuated neuropathic pain by inhibiting mTOR to induce autophagy in SNL neuropathic pain model. The aim of this study was to evaluate the role of AKT/TSC2/mTOR pathway in SNL and autophagy and determine whether HBO treatment could relieve neuropathic pain via modulating AKT/TSC2/mTOR pathway.
Learn More >Spinal cord stimulation (SCS) relieves pain by delivering doses of electric current to the dorsal column of the spinal cord and has been found to be most effective in the treatment of neuropathic pain. Psychological distress is a significant risk factor for the development of chronic pain and has been found to affect the outcome of SCS. Childhood trauma is a risk factor for chronic pain, but has not previously been studied in SCS patients.
Learn More >Chronic headache (headache ≥15 days/month) is a leading cause of disability. Illness perception, beliefs and cognitive models are likely central for patient understanding of their chronic pain condition and are associated with treatment outcome. However, these factors are insufficiently described in chronic headache.
Learn More >Type A γ-aminobutyric acid (GABA) receptors are pentameric ligand-gated ion channels and the main drivers of fast inhibitory neurotransmission in the vertebrate nervous system. Their dysfunction is implicated in a range of neurological disorders, including depression, epilepsy and schizophrenia. Among the numerous assemblies that are theoretically possible, the most prevalent in the brain are the α1β2/3γ2 GABA receptors. The β3 subunit has an important role in maintaining inhibitory tone, and the expression of this subunit alone is sufficient to rescue inhibitory synaptic transmission in β1-β3 triple knockout neurons. So far, efforts to generate accurate structural models for heteromeric GABA receptors have been hampered by the use of engineered receptors and the presence of detergents. Notably, some recent cryo-electron microscopy reconstructions have reported 'collapsed' conformations; however, these disagree with the structure of the prototypical pentameric ligand-gated ion channel the Torpedo nicotinic acetylcholine receptor, the large body of structural work on homologous homopentameric receptor variants and the logic of an ion-channel architecture. Here we present a high-resolution cryo-electron microscopy structure of the full-length human α1β3γ2L-a major synaptic GABA receptor isoform-that is functionally reconstituted in lipid nanodiscs. The receptor is bound to a positive allosteric modulator 'megabody' and is in a desensitized conformation. Each GABA receptor pentamer contains two phosphatidylinositol-4,5-bisphosphate molecules, the head groups of which occupy positively charged pockets in the intracellular juxtamembrane regions of α1 subunits. Beyond this level, the intracellular M3-M4 loops are largely disordered, possibly because interacting post-synaptic proteins are not present. This structure illustrates the molecular principles of heteromeric GABA receptor organization and provides a reference framework for future mechanistic investigations of GABAergic signalling and pharmacology.
Learn More >In western countries, lower back pain (LBP) is one of the most common disorders, experienced by more than 80% of the population. Chronic LBP due to disc degeneration has been linked to ongoing inflammatory processes in the disc and endplates. Pain effects the body in different ways, inducing a general stress response in which the body responds by releasing the stress hormone cortisol. Little is known about the impact of pain-induced stress on the progression of disc degeneration. Thus, the effects of cortisol on disc cells (DCs) and human mesenchymal stem cells (hMSCs) were explored in vitro with the objective of investigating the repercussions of cortisol on these cell types involved in de- and regenerative mechanisms of the disc. DC and hMSC pellet cultures were exposed to cortisol at two concentrations (150 and 300 ng/mL) for 28 days to simulate pain-induced stress. Cell viability, histological staining, and GAG DNA, along with apo-ptotic assays were conducted. Detection of OCT4, SOX9, IL-1R, and CXCR2 expressions was performed by immunohistochemistry. With cortisol treatment, restricted cell proliferation and less GAG production in both DCs and hMSCs were observed. Suppression of the differentiation and immunomodulatory efficacy of hMSCs was also detected. Moreover, elevated expressions of IL-1R and CXCR2 were detected in both cell types. To conclude, constant exposure to cortisol even at a physiological level enhanced pathological cellular processes in both DCs and hMSCs, which further jeopardized chondrogenesis. This suggests that cortisol resulting from pain-induced stress is a contributing component of intervertebral disc degeneration and may negatively affect regenerative attempts of the disc.
Learn More >In 2016, a special interest group from the International Forum for the Study of Itch defined sensitive skin (SS) as a syndrome that manifests with the occurrence of unpleasant sensations (stinging, burning, pain, pruritus, and tingling sensations) after stimuli that should not cause a reaction, such as water, cold, heat, or other physical and/or chemical factors. The pathophysiology of sensitive skin is still poorly understood, but the symptoms described suggest inflammation and peripheral innervation. Only two publications have focused on sensitive skin transcriptomics. In the first study, the authors performed a microarray comparison of SS and non-sensitive skin (NSS) samples and showed differences in the expression of numerous genes in SS and NSS samples. Moreover, in the SS samples, two clusters of genes were identified, including upregulated and downregulated genes, compared to NSS samples. These results provide some interesting clues for the understanding of the pathophysiology of SS. The second study compared SS and NSS samples using RNA-seq assays. This method allowed the identification of long non-coding RNAs (lncRNAs) and differentially expressed mRNAs and provided a comprehensive profile in subjects with SS. The results showed that a wide range of genes may be involved in the pathogenesis of SS and suggested pathways that could be associated with them. In this paper, we discuss these two studies in detail and show how transcriptomic studies can help understand the pathophysiology of sensitive skin. We call for new transcriptomic studies on larger populations to be conducted before putative pathogenic mechanisms can be detected and analyzed to achieve a better understanding of this complex condition.
Learn More >