numbers of cells under various dietary regimens in relation to the APOE genotype. Our results are in agreement with previous investigations that showed APOE 34 to be associated with higher levels of the anti-inflammatory and immunomodulatory vitamin D and adiponectin. 2 In addition, levels of C-reactive protein are lower in APOE 34 carriers versus noncarriers, 8 which may be indicative of an anti-inflammatory milieu. In summary, all these findings suggest a protective role of APOE 34 in metabolic disorders. Indeed, in a recent study, WD feeding led to higher insulin and plasma lipid levels, impaired glucose tolerance, and higher body weights in APOE 33/33 versus APOE 34/34 mice, 9 although contrasting findings exist. 3 Human studies are still rare and inconclusive. We hope that our data stimulate further research into the role of the APOE genotype in metabolic disorders.
Pain is a protective mechanism that enables us to avoid potentially harmful environments. However, when pathologically persisted and aggravated under severely injured or inflamed conditions, pain often reduces the quality of life and thus is considered as a disease to eliminate. Inflammatory and/or neuropathic mechanisms may exaggerate interactions between damaged tissues and neural pathways for pain mediation. Similar mechanisms also promote the communication among cellular participants in synapses at spinal or higher levels, which may amplify nociceptive firing and subsequent signal transmission, deteriorating the pain sensation. In this pathology, important cellular players are afferent sensory neurons, peripheral immune cells, and spinal glial cells. Arising from damage of injury, overloaded interstitial and intracellular reactive oxygen species (ROS) and intracellular Ca are key messengers in the development and maintenance of pathologic pain. Thus, an ROS-sensitive and Ca-permeable ion channel that is highly expressed in the participant cells might play a critical role in the pathogenesis. Transient receptor potential melastatin subtype 2 (TRPM2) is the unique molecule that satisfies all of the requirements: the sensitivity, permeability, and its expressing cells. Notable progress in delineating the role of TRPM2 in pain has been achieved during the past decade. In the present review, we summarize the important findings in the key cellular components that are involved in pathologic pain. This overview will help to understand TRPM2-mediated pain mechanisms and speculate therapeutic strategies by utilizing this updated information.
Modulation of the function of somatosensory neurons is an important analgesic strategy, requiring the proposal of novel molecular targets. Many G-protein-coupled receptors (GPRs) have been deorphanized, but the receptor locations, outcomes due to their activations, and their signal transductions remain to be elucidated, regarding the somatosensory nociceptor function. Here we report that GPR171, expressed in a nociceptor subpopulation, attenuated pain signals via Gi/o-coupled modulation of the activities of nociceptive ion channels when activated by its newly found ligands. Administration of its natural peptide ligand and a synthetic chemical ligand alleviated nociceptor-mediated acute pain aggravations and also relieved pathologic pain at nanomolar and micromolar ranges. This study suggests that functional alteration of the nociceptor neurons by GPR171 signaling results in pain alleviation and indicates that GPR171 is a promising molecular target for peripheral pain modulation.
Biological effects of suberanilohydroxamic acid (SAHA) have mainly been observed in the context of tumor suppression via epigenetic mechanisms, but other potential outcomes from its use have also been proposed in different fields such as pain modulation. Here, we tried to understand whether SAHA modulates specific pain modalities by a non-epigenetic unknown mechanism. From 24 h Complete Freund's Adjuvant (CFA)-inflamed hind paws of mice, mechanical and thermal inflammatory pain indices were collected with or without immediate intraplantar injection of SAHA. To examine the action of SAHA on sensory receptor-specific pain, transient receptor potential (TRP) ion channel-mediated pain indices were collected in the same manner of intraplantar treatment. Activities of primarily cultured sensory neurons and heterologous cells transfected with TRP channels were monitored to determine the molecular mechanism underlying the pain-modulating effect of SAHA. As a result, immediate and localized pretreatment with SAHA, avoiding an epigenetic intervention, acutely attenuated mechanical inflammatory pain and receptor-specific pain evoked by injection of a TRP channel agonist in animal models. We show that a component of the mechanisms involves TRPV4 inhibition based on in vitro intracellular Ca imaging and electrophysiological assessments with heterologous expression systems and cultured sensory neurons. Taken together, the present study provides evidence of a novel off-target action and its mechanism of SAHA in its modality-specific anti-nociceptive effect and suggests the utility of this compound for pharmacological modulation of pain.
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