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Bone cancer pain (BCP) caused by primary or metastatic bone tumours significantly interferes with the quality of life of patients. However, the relief of BCP remains a major challenge. Our previous study demonstrated that intrathecal administration of the Sirtuin 1 (SIRT1) activator SRT1720 attenuated BCP in a murine model. Nevertheless, the underlying mechanisms have not been fully clarified. Previous studies demonstrated that the activation of the cAMP response element binding (CREB) protein played a critical role in BCP. Furthermore, SIRT1 can also regulate the balance between glucose and lipid metabolism through CREB deacetylation. In this study, we measured the analgesic effects of different intrathecal doses of SRT1720 on BCP in a murine model and further examined whether SRT1720 attenuated BCP by suppressing CREB/CREB-regulated transcription coactivator 1 (CRTC1) signalling pathway. Our results demonstrated that the BCP mice developed significant mechanical allodynia and spontaneous flinching, which were accompanied by the upregulation of phospho-Ser133 CREB (p-CREB) and CRTC1 expression in the spinal cord. SRT1720 treatment produced a dose-dependent analgesic effect on the BCP mice and downregulated the expression of p-CREB and CRTC1. These results suggest that intrathecal administration of SRT1720 reverses BCP likely by inhibiting the CREB/CRTC1 signalling pathway.
Learn More >Paradoxically, some TRPV1 agonists are, at the organismal level, both non-pungent and clinically useful as topical analgesics. Here, we describe the scaled-up synthesis and characterization in mouse models of a novel, non-pungent vanilloid. Potent analgesic ac-tivity was observed in models of neuropathic pain, and the compound blocked capsaicin induced allodynia, showing dermal accu-mulation with little transdermal absorption. Finally, it displayed much weaker systemic toxicity compared to capsaicin and was negative in assays of genotoxicity.
Learn More >The United States is experiencing an epidemic of opioid use disorder (OUD) and overdose-related deaths. However, the genetic basis for the ability to discontinue opioid use has not been investigated. We performed a genome-wide association study (GWAS) of opioid cessation (defined as abstinence from illicit opioids for >1 year or <6 months before the interview date) in 1130 African American (AA) and 2919 European ancestry (EA) participants recruited for genetic studies of substance use disorders and who met lifetime Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for OUD. Association tests performed separately within each ethnic group were combined by meta-analysis with results obtained from the Comorbidity and Trauma Study. Although there were no genome-wide significant associations, we found suggestive associations with nine independent loci, including three which are biologically relevant: rs4740988 in ( = 2.24 × 10), rs36098404 in ( = 2.24 × 10), and rs592026 in ( = 6.53 × 10). Significant pathways identified in persons of European ancestry (EA) are related to vitamin D metabolism ( = 3.79 × 10) and fibroblast growth factor (FGF) signaling ( = 2.39 × 10). UK Biobank traits including smoking and drinking cessation and chronic back pain were significantly associated with opioid cessation using GWAS-derived polygenic risk scores. These results provide evidence for genetic influences on opioid cessation, suggest genetic overlap with other relevant traits, and may indicate potential novel therapeutic targets for OUD.
Learn More >Cluster headache (CH) is a severe primary headache with a prevalence of 1/1000 individuals, and a predominance in men. Calcitonin gene-related peptide (CGRP) is a potent vasodilator, originating in trigeminal neurons and has a central role in CH pathophysiology. CGRP and the CGRP receptor complex have recently taken center stage as therapeutic targets for primary headaches, such as migraine. Multiple CGRP and CGRP receptor monoclonal antibodies, as well as small molecule antagonists (gepants) are on their way constituting a new frontier of migraine and possibly CH medication. During a CH attack, there is an activation of the trigeminal-autonomic reflex with the release of CGRP, and inversely if CGRP is administered to a CH patient in an active disease phase, it triggers an attack. Increased levels of CGRP have been found in ipsilateral jugular vein blood during the active phase of CH. This process is hypothesized to have a key role in the intense pain perception and in the associated distinctive vasodilation. So far, clinical tests of CGRP antibodies have been inconclusive in CH patients. This review summarizes the current state of knowledge on the role of CGRP in CH pathology, and as a target for future treatments.
Learn More >The dorsal striatum, apart from controlling voluntary movement, displays a recently demonstrated pain inhibition. It is connected to the descending pain modulatory system and in particular to the rostral ventromedial medulla through the medullary dorsal reticular nucleus. Diseases of the basal ganglia, such as Parkinson's disease, in addition to being characterized by motor disorders, are associated with pain and hyperactivation of the excitatory transmission. A way to counteract glutamatergic hyperactivation is through the activation of group III metabotropic glutamate receptors (mGluRs), which are located on presynaptic terminals inhibiting neurotransmitter release. So far the mGluRs of group III have been the least investigated, owing to a lack of selective tools. More recently, selective ligands for each mGluR of group III, in particular positive and negative allosteric modulators, have been developed and the role of each subtype is starting to emerge. The neuroprotective potential of group III mGluRs in pathological conditions, such as those characterized by elevate glutamate, has been recently shown. In the dorsal striatum mGluR7 and mGluR8 are located at glutamatergic corticostriatal terminals and their stimulation inhibits pain in pathological conditions such as neuropathic pain. The two receptors in the dorsal striatum have instead a different role on pain control in normal conditions. This review will discuss recent results focusing on the contribution of mGluR7 and mGluR8 in the dorsal striatal control of pain. The role of mGluR4, whose antiparkinsonian activity is widely reported, will be also addressed.
Learn More >Psychiatric disorders such as anxiety and depression are frequently observed in neuropathic pain patients, and negatively impact their quality of life. Mirogabalin is a novel ligand for the αδ subunit of voltage-gated calcium channels and has unique binding characteristics to αδ subunits and potent and long-lasting analgesic effects in neuropathic pain models.
Learn More >This updated systematic review evaluated the efficacy, tolerability and safety of opioids compared to placebo in chronic non-cancer neuropathic pain.
Learn More >The aim of this study was to analyze the potential association between personality traits and onabotulinumtoxin A (onabotA) response in patients with chronic migraine (CM).
Learn More >Evaluate changes from baseline in health-related quality of life (QoL) in Japanese patients with episodic migraine receiving preventive treatment with galcanezumab (GMB).
Learn More >Oliceridine, an investigational IV opioid, is a first-in-class G-protein selective agonist at the -opioid receptor. The G-protein selectivity results in potent analgesia with less recruitment of -arrestin, a signaling pathway associated with opioid-related adverse events (ORAEs). In randomized controlled studies in both hard and soft tissue models yielding surgical pain, oliceridine provided effective analgesia with a potential for an improved safety and tolerability profile at equianalgesic doses to morphine. The phase 3, open-label, single-arm, multicenter ATHENA trial demonstrated the safety, tolerability, and effectiveness of oliceridine in moderate to severe acute pain in a broad range of patients undergoing surgery or with painful medical conditions warranting use of an IV opioid. This retrospective, observational chart review study compared respiratory depression events associated with oliceridine administration as found in the ATHENA trial to a control cohort treated with conventional opioids.
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