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Pain is one of the first presenting symptoms in patients with head and neck cancer, who often develop chronic and debilitating pain as the disease progresses. Pain is also an important prognostic marker for survival. Unfortunately, patients rarely receive effective pain treatment due to our limited knowledge of the mechanisms underlying head and neck cancer pain (HNCP). Pain is often associated with neuroinflammation and particularly interleukin (IL)-1 signaling. The purpose of this study is to develop a novel syngeneic model of HNCP in immunocompetent mice to examine the contribution of IL-1 signaling.
Learn More >Neurosurgical treatments for trigeminal neuralgia (TN) can provide long-lasting pain relief, however, some patients fail to respond and undergo multiple, repeat procedures. Surgical outcomes can vary depending on the type of TN, but the reasons for this are not well understood. Neuroimaging studies of TN point to abnormalities in the brainstem trigeminal fibers, however, whether this is a common characteristic of treatment non-response across different subtypes of TN is unknown. Here, we used diffusion tensor imaging (DTI) to determine whether the brainstem trigeminal fiber microstructure is a common biomarker of surgical response in TN and whether the extent of these abnormalities is associated with the likelihood of response across subtypes of TN. We studied 98 patients with TN (61 classical TN, 26 TN secondary to multiple sclerosis, and 11 TN associated with a solitary pontine lesion) who underwent neurosurgical treatment and 50 healthy controls. We assessed treatment response using pain intensity measures and examined microstructural features by extracting pre-treatment DTI metrics from the proximal pontine segment of the trigeminal nerves. We found that microstructural abnormalities in the affected pontine trigeminal fibers (notably, lower fractional anisotropy and higher radial diffusivity) highlight treatment non-responders (n=47) compared to responders (n=51) and controls, and that the degree of abnormalities is associated with the likelihood of surgical response across subtypes of TN. These novel findings demonstrate the value of DTI as an objective, non-invasive tool for the prediction of treatment response and elucidate the features that distinguish treatment responders from non-responders in the TN population.
Learn More >Osteoarthritis (OA) is the most common joint disease and leading cause of pain and disability in the elderly population. Most guidelines recommend the use of non-steroidal anti-inflammatory drugs (NSAIDs) and opioids for the non-operative treatment of OA. Monoclonal nerve growth factor (NGF) antibodies are new drugs with the potential to provide pain relief and functional improvement in OA. We compared the efficacy (pain reduction and functional improvement), and safety of monoclonal NGF antibodies with NSAIDs and opioids in the treatment of OA with a Bayesian network meta-analysis.
Learn More >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.
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