Sunday, August 7, 2016

Pain and fatigue and being female: ASIC3 channels

We have acid sensors in our body that detects a drop in pH which is involved in pain perception (among other things).

"Acid-sensing ion channels (ASICs) can detect a broad range of physiological pH changes during pathological and synaptic cellular activities...Activation of ASICs is involved in pain perception, synaptic plasticity, learning and memory, fear, ischemic neuronal injury, seizure termination, neuronal degeneration, and mechanosensation. Therefore, ASICs emerge as potential therapeutic targets for manipulating pain and neurological diseases. The activity of these channels can be regulated by many factors such as lactate, Zn2+, and Phe-Met-Arg-Phe amide (FMRFamide)-like neuropeptides by interacting with the channel’s large extracellular loop. ASICs are also modulated by G protein-coupled receptors such as CB1 cannabinoid receptors and 5-HT2. This review focuses on the physiological roles of ASICs and the molecular mechanisms by which these channels are regulated." http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133903/

Estrogen can potentiate the action of ASICs.

"E2 potentiated ASIC currents via an ERα and ERK1/2 signaling pathway. E2 also altered acidosis-evoked membrane excitability of dorsal root ganglia neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acidic stimuli. E2 potentiation of the functional activity of ASICs revealed a peripheral mechanism underlying this sex difference in acetic acid-induced nociception."  http://press.endocrine.org/doi/abs/10.1210/en.2015-1557?journalCode=endo#sthash.0DpqNTD7.dpuf

Pain causes fatigue through similar means. Testosterone seems to lessen this effect.

"Chronic pain and fatigue often occur together -- as many as three in four people with chronic, widespread musculoskeletal pain report having fatigue; and as many as 94 percent of people with chronic fatigue syndromes report muscle pain. Women make up the majority of patients with these conditions..."The differences in fatigue between males and females depends on both the presence of testosterone and the activation of ASIC3 channels, which suggests that they are interacting somehow to protect against fatigue," Sluka said. "These differences may help explain some of the underlying differences we see in chronic pain conditions that include fatigue with respect to the predominance of women over men."" https://www.sciencedaily.com/rel.../2008/04/080407153037.htm

Endometriosis is an inflammatory condition and ASIC play a role in inflammation.

"Microglia, the major immune cells in central nervous system, act as the surveillance and scavenger of immune defense and inflammatory response. Previous studies suggest that there might be close relationship between acid-sensing ion channels (ASICs) and inflammation, however, the exact role of ASICs in microglia during inflammation remains elusive...Taken together, these results suggest that ASICs participate in neuroinflammatory response, which will provide a novel therapeutic strategy for controlling the inflammation-relevant neuronal diseases." http://www.ncbi.nlm.nih.gov/pubmed/25377529 

"Nonsteroid anti-inflammatory drugs (NSAIDs) are major drugs against inflammation and pain. They are well known inhibitors of cyclooxygenases (COXs). However, many studies indicate that they may also act on other targets. Acidosis is observed in inflammatory conditions such as chronic joint inflammation, in tumors and after ischemia, and greatly contributes to pain and hyperalgesia. Administration of NSAIDs reduces low-pH-induced pain." http://www.jneurosci.org/content/21/20/8026.long

"ASICs (Acid Sensing Ion Channels) are of particular interest because they are directly activated by extracellular acidity, which is a major cause of pain. Indeed, many painful conditions such as ischemia, inflammation, tumor development or tissue incision are accompanied by tissue acidification. ASIC are excitatory ion channels that are expressed in neurons, including nociceptive sensory neurons. In humans, the use of amiloride, a nonspecific inhibitor of ASICs, has demonstrated their role in the perception of pain induced by subcutaneous injections of acidic solutions. ASICs thus appear as new candidates capable of mediating pain in humans. A growing number of data suggests that, in addition to protons, ASICs may also be activated by one or more endogenous compounds produced during inflammation. The purpose of this research project is to identify these compounds by testing the effects of human inflammatory exudates on ASICs activity. The discovery of such compounds would definitely validate ASICs as novel therapeutic targets for pain treatment in humans." https://clinicaltrials.gov/ct2/show/NCT01867840



Wednesday, February 17, 2016

Endo and immune system

The presence of endometriosis can cause disruption in the immune system:

"In the genetic regulation of Müllerian structures development, a key role is played by Hoxa and Wnt clusters, because they lead the transcription of different genes according to the different phases of the organogenesis, addressing correctly cell-to-cell interactions, allowing, finally, the physiologic morphogenesis. Accumulating evidence is suggesting that dysregulation of Wnt and/or Hox genes may affect cell migration during organogenesis and differentiation of Müllerian structures of the female reproductive tract, with possible dislocation and dissemination of primordial endometrial stem cells in ectopic regions, which have high plasticity to differentiation. We hypothesize that during postpubertal age, under the influence of different stimuli, these misplaced and quiescent ectopic endometrial cells could acquire new phenotype, biological functions, and immunogenicity. So, these kinds of cells may differentiate, specializing in epithelium, glands, and stroma to form a functional ectopic endometrial tissue. This may provoke a breakdown in the peritoneal cavity homeostasis, with the consequent processes of immune alteration, documented by peripheral mononuclear cells recruitment and secretion of inflammatory cytokines in early phases and of angiogenic and fibrogenic cytokines in the late stages of the disease." http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3697788/#!po=2.17391