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Osteoarthritis (OA) is the most common cause of joint pain. Animal models and relevant assays for measurement of pain-related behaviours are important tools for studies of mechanisms inducing and sustaining pain in OA. The aim of this study was to evaluate two different assessments of weight bearing; stationary and during locomotion, and to explore their feasibility to detect analgesic effects in vivo. Two fundamentally different mouse models of joint arthritis were investigated; surgical transection of the anterior cruciate ligament (ACLT) resulting in destabilization of the joint with subsequent structural deterioration resembling OA, and monoarthritis induced by injection of Complete Freund´s Adjuvant (CFA) into the ankle joint capsule.
We tested the hypothesis that high molecular weight hyaluronan (HMWH) binds to and signals via cluster of differentiation 44 receptor (CD44), to attenuate nociceptor function, in the setting of inflammation. We found that HMWH attenuates prostaglandin E (PGE)-induced mechanical hyperalgesia, in male and female rats. Intrathecal administration of an oligodeoxynucleotide antisense to CD44 mRNA and intradermal administration of A5G27, a CD44 receptor antagonist, both attenuate anti-hyperalgesia induced by HMWH. HMWH signaling is dependent on CD44 clustering in lipid rafts, leading to activation of downstream second messenger signaling pathways. Methyl-β-cyclodextrin (MβCD), which disrupts lipid rafts, attenuates HMWH-induced anti-hyperalgesia. Inhibitors for components of intracellular signaling pathways activated by CD44, phospholipase C (PLC) and phosphoinositide 3-kinase (PI3K), also attenuates HMWH-induced anti-hyperalgesia. Our results demonstrate the central role of CD44 in HMWH-induced anti-hyperalgesia and establish its second messengers as novel therapeutic targets for the treatment of pain.We have previously demonstrated that high molecular weight hyaluronan (HMWH) attenuates inflammatory and neuropathic hyperalgesia. In this study we demonstrate that HMWH attenuates PGE-hyperalgesia is mediated by its action at CD44, and activation of its downstream signaling pathways, including RhoGTPases (RhoA and Rac1) and phospholipases (phospholipases Cε and Cγ1), in nociceptors of male and female rats. These findings contribute to our understanding of the anti-hyperalgesic effect of HMWH and support the hypothesis that CD44 and its downstream signaling pathways represent novel therapeutic targets for the treatment of inflammatory pain.
Treatment for fibromyalgia is an unmet medical need; however, its pathogenesis is still poorly understood. In a series of studies, we have demonstrated that some pharmacological treatments reverse generalized chronic pain, but do not affect the lack of morphine analgesia in the intermittent cold stress (ICS)-induced fibromyalgia-like pain model in mice. Here we report that repeated intraperitoneal treatments with mirtazapine (Mir), which is presumed to disinhibit 5-HT release and activate 5-HT1 receptor through mechanisms of blocking presynaptic adrenergic α2, postsynaptic 5-HT2 and 5-HT3 receptors, completely reversed the chronic pain for more than 4-5 days after the cessation of treatments. The repeated Mir-treatments also recovered the morphine analgesia after the return of nociceptive threshold to the normal level. The microinjection of siRNA adrenergic α2a receptor (ADRA2A) into the habenula, which showed a selective upregulation of α2 receptor gene expression after ICS, reversed the hyperalgesia, but did not recover the morphine analgesia. However, both reversal of hyperalgesia and recovery of morphine analgesia were observed when siRNA ADRA2A was administered intracebroventricularly. As the habenular is reported to be involved in the emotion/reward-related pain and hypoalgesia, these results suggest that Mir could attenuate pain and/or augment hypoalgesia by blocking the habenular α2 receptor after ICS. The recovery of morphine analgesia in the ICS model, on the other hand, seems to be mediated through a blockade of α2 receptor in unidentified brain regions. SIGNIFICANCE STATEMENT: This study reports possible mechanisms underlying the complete reversal of hyperalgesia and recovery of morphine analgesia by mirtazapine, a unique antidepressant with adrenergic α2 and serotonergic receptor antagonist properties, in a type of intermittently repeated stress (ICS)-induced fibromyalgia-like pain model. Habenula, a brain region which is related to the control of emotional pain, was found to play key roles in the anti-hyperalgesia, while other brain regions appeared to be involved in the recovery of morphine analgesia in the ICS-model.
Evidence from several novel opioid agonists and knockout animals suggest that improved opioid therapeutic window, notably for analgesia versus respiratory depression, can be caused by ligand bias downstream of activation of the mu-opioid receptor (MOR) towards G-protein signaling and away from other pathways such as arrestin recruitment. Here, we argue that published claims of opioid bias based on application of the operational model of agonism are frequently confounded by failure to consider the assumptions of the model. These include failure to account for intrinsic efficacy and ceiling effects in different pathways, distortions introduced by analysis of amplified (G-protein) versus linear (arrestin) signaling mechanisms, and non-equilibrium effects in a dynamic signaling cascade. We show on both theoretical and experimental grounds that reduced intrinsic efficacy that is unbiased across different downstream pathways does produce apparent but erroneous MOR ligand bias towards G-protein signaling, and the weaker the G-protein partial agonism the greater is the apparent bias. Experimentally, such apparently G-protein biased opioids have been shown to exhibit low intrinsic efficacy for G-protein signaling when ceiling effects are properly accounted for. Nevertheless, such agonists do display an improved therapeutic window for analgesia versus respiratory depression. Reduced intrinsic efficacy for G-proteins rather than any supposed G-protein bias provides a more plausible, sufficient explanation for the improved safety. Moreover, genetic models of G-protein biased opioid receptors and replication of previous knockout experiments suggest that reduced or abolished arrestin recruitment does not improve therapeutic window for analgesia versus respiratory depression. SIGNIFICANCE STATEMENT: Efforts to improve safety of mu-opioid analgesics has focused on agonists that show signaling bias for the G-protein pathway versus other signaling pathways. This review provides theoretical and experimental evidence showing that failure to properly consider the assumptions of the operational model of bias commonly leads to large distortions and overestimation of actual bias. We show that low intrinsic efficacy is a major determinant of these distortions and pursuit of appropriately reduced intrinsic efficacy should lead development of safer opioids.
Activated astrocytes play important roles in chronic post-surgical pain (CPSP). Recent studies have shown reactive astrocytes are classified into A1 and A2 phenotypes, but their precise roles in CPSP remain unknown. In this study, we investigated the roles of spinal cord A1 and A2 astrocytes and related mechanisms in CPSP.
According to the International Classification of Headache Disorders 3, post-traumatic headache (PTH) attributed to traumatic brain injury (TBI) is a secondary headache reported to have developed within 7 days from head injury, regaining consciousness following the head injury, or discontinuation of medication(s) impairing the ability to sense or report headache following the head injury. It is one of the most common secondary headache disorders, and it is defined as persistent when it lasts more than 3 months.
The voltage-gated sodium channel Nav1.7 is essential for adequate perception of painful stimuli. Mutations in the encoding gene, SCN9A, cause various pain syndromes in human patients. The hNav1.7/A1632E mutant causes symptoms of erythromelalgia and paroxysmal extreme pain disorder (PEPD), and its main gating change is a strongly enhanced persistent current. On the basis of recently published 3D structures of voltage-gated sodium channels, we investigated how the inactivation particle binds to the channel, how this mechanism is interfered with by the hNav1.7/A1632E mutation, and how dimerization modifies function of the pain-linked mutation.
Spinal pain is the leading worldwide cause of patient-years lived with chronic pain and disability. While opioids are well documented as an effective short-term pain-relieving medication, more than a few weeks of treatment may result in a diminishing clinical effect as well as the development of addictive behavior. Even though opioid addiction in pain patients is a major problem commonly experienced in the clinic, no reference material exists on the scope of long-term problems in novel opioid users and the link to clinical outcomes.
To identify baseline characteristics of adults with chronic low back pain (cLBP) that predict response (i.e., a clinically important improvement) and/or modify treatment effect across three nonpharmacologic interventions.
Agonists to the μ-opioid G protein-coupled receptor (μOR) can alleviate pain through activation of G protein signaling, but they can also induce β-arrestin activation, leading to such side effects as respiratory depression. Biased ligands to μOR that induce G protein signaling without inducing β-arrestin signaling can alleviate pain while reducing side effects. However, the mechanism for stimulating β-arrestin signaling is not known, making it difficult to design optimum biased ligands. We use extensive molecular dynamics simulations to determine three-dimensional (3D) structures of activated β-arrestin2 stabilized by phosphorylated μOR bound to the morphine and D-Ala, -MePhe, Gly-ol]-enkephalin (DAMGO) nonbiased agonists and to the TRV130 biased agonist. For nonbiased agonists, we find that the β-arrestin2 couples to the phosphorylated μOR by forming strong polar interactions with intracellular loop 2 (ICL2) and either the ICL3 or cytoplasmic region of transmembrane (TM6). Strikingly, Gi protein makes identical strong bonds with these same ICLs. Thus, the Gi protein and β-arrestin2 compete for the same binding site even though their recruitment leads to much different outcomes. On the other hand, we find that TRV130 has a greater tendency to bind the extracellular portion of TM2 and TM3, which repositions TM6 in the cytoplasmic region of μOR, hindering β-arrestin2 from making polar anchors to the ICL3 or to the cytosolic end of TM6. This dramatically reduces the affinity between μOR and β-arrestin2.