Browse by Audience
Heterologous sensitization of adenylyl cyclase (AC) is defined by an enhanced cAMP response following persistent activation of Gα-coupled receptors. This phenomenon was first observed in cellular models, and later reported in animal models of inflammatory pain or following chronic exposure to drugs of abuse including opioids and cocaine. Recently, we used genome-wide siRNA screening to identify Cullin3 signaling as a mediator of AC sensitization in cellular models. We also showed that pharmacological inhibition of Cullin3 with the neddylation inhibitor, MLN4924, abolished heterologous sensitization of several AC isoforms, including AC1, AC2, AC5, and AC6. Because ACs, especially AC1, have been implicated in alcohol-induced locomotor sensitization and inflammatory pain, we assessed the potential activity of MLN4924 in both murine models. We found that MLN4924 (30 mg/kg, i.p.) accumulated in the brain and reduced both locomotor sensitization induced by repeated alcohol administration and allodynia in an inflammatory pain model. Based on our previous findings that MLN4924 potently blocks AC sensitization in cellular models, we propose that the activity of MLN4924 in both animal models potentially occurs through blocking AC sensitization. Our findings provide the basis for understanding the molecular mechanism and yield a new pathway for drug development for pathological disorders associated with AC sensitization.
Learn More >Improving end of life (EOL) care for children with complex chronic conditions (CCCs) requires parental perspectives. The vulnerability of bereaved parents has historically been a research barrier and studies describing their research participation experience are lacking.
Learn More >Chronic pain is a hallmark of functional disorders, inflammatory diseases and cancer of the digestive system. The mechanisms that initiate and sustain chronic pain are incompletely understood, and available therapies are inadequate. This review highlights recent advances in the structure and function of pronociceptive and antinociceptive G protein-coupled receptors (GPCRs) that provide insights into the mechanisms and treatment of chronic pain. This knowledge, derived from studies of somatic pain, can guide research into visceral pain. Mediators from injured tissues transiently activate GPCRs at the plasma membrane of neurons, leading to sensitisation of ion channels and acute hyperexcitability and nociception. Sustained agonist release evokes GPCR redistribution to endosomes, where persistent signalling regulates activity of channels and genes that control chronic hyperexcitability and nociception. Endosomally targeted GPCR antagonists provide superior pain relief in preclinical models. Biased agonists stabilise GPCR conformations that favour signalling of beneficial actions at the expense of detrimental side effects. Biased agonists of µ-opioid receptors (MOPrs) can provide analgesia without addiction, respiratory depression and constipation. Opioids that preferentially bind to MOPrs in the acidic microenvironment of diseased tissues produce analgesia without side effects. Allosteric modulators of GPCRs fine-tune actions of endogenous ligands, offering the prospect of refined pain control. GPCR dimers might function as distinct therapeutic targets for nociception. The discovery that GPCRs that control itch also mediate irritant sensation in the colon has revealed new targets. A deeper understanding of GPCR structure and function in different microenvironments offers the potential of developing superior treatments for GI pain.
Learn More >Post-traumatic headache (PTH) is one of the most common and long-lasting symptoms following mild traumatic brain injury (TBI). However, the pathological mechanisms underlying the development of persistent PTH remain poorly understood. The primary purpose of this prospective pilot study was to evaluate whether early pain modulatory profiles (sensitization and endogenous pain inhibitory capacity) and psychological factors after mild TBI predict the development of persistent PTH in mild TBI patients.
Learn More >Migraine remains a challenging condition to treat, thus highlighting the need for a better understanding of its molecular mechanisms. This review intends to unravel a new emerging target in migraine pathophysiology, the adenosine 5'-triphosphate-sensitive K (K) channel.
Learn More >The prevalence of migraine and non-migraine headache declines with age.
Learn More >Recently, amylin and its receptors were found in different structures involved in migraine pathophysiology. Here, we evaluate interictal concentrations of amylin and calcitonin gene-related peptide in peripheral blood as biomarkers for chronic migraine.
Learn More >To determine reversion rates from chronic migraine to episodic migraine during long-term erenumab treatment.
Learn More >To describe longitudinal patterns of medication use throughout pregnancy in women with migraine.
Learn More >To identify the correlation between cathodal transcranial direct current stimulation (tDCS) and the power spectral density (PSD) of alpha-band on the occipital lobe of migraineurs.
Learn More >