Pain, in the sense of physical pain, is a typical sensory experience that may be described as the unpleasant awareness of a noxious stimulus or bodily harm
Pain Genes, 2008
Recent advances in the management of chronic stable angina II. Anti-ischemic therapy, options for refractory angina, risk factor reduction, and revascularization, 2010
Anti-ischemic therapy includes the use of 3 traditional antianginal agents: nitrates, β-blockers, and calcium channel blockers (CCBs). Traditional agents lower anginal symptoms and prolong exercise duration and/or time to ST-segment depression on the electrocardiogram (ECG). Frequently a combination of these drugs is necessary for symptom control. However, none of these drugs have been shown to be disease modifying – their use does not change the risk of MI, sudden cardiac death, or all-cause mortality. Their mechanism of action is the reduction of myocardial oxygen demand (heart rate, afterload, and preload) so that the threshold producing anginal symptoms is not reached (see Part I of this series1). In practice, this translates to lowering rate-pressure product and/or producing systemic venodilation, thereby lowering left ventricular end-diastolic pressure (LV-EDP) and volume and reducing myocardial wall tension. In turn, this permits greater flow in the epicardial coronary arteries and improves myocardial oxygen delivery. Relative advantages of each agent with respect to cardiac physiology and patient comorbidities permit partial customization of therapy.
Nitroglycerin, in clinical use since 1878, causes dilation of epicardial coronary arteries, even when they are partially stenosed, by relaxing arterial smooth muscle. Nitroglycerin does not release nitric oxide (NO) directly, as compared with sodium nitroprusside. The organic nitrates react with intracellular sulfhydryl groups (eg, from methionine or cysteine) and enzymes to produce NO or the intermediate S-nitrosothiol, which is reduced to NO. Thus, nitrates are prodrugs that undergo enzymatic denitrification within the vascular wall, most significantly by mitochondrial aldehyde dehydrogenase. NO then activates smooth muscle guanylyl cyclase, raising cyclic guanosine monophosphate (cGMP) levels to inhibit calcium entry into the muscle cell and relax muscle filaments. NO also acts to inhibit potassium channels, hyperpolarizing muscle membranes, and activating light chain phosphatase, both of which effect relaxation, and may account for a significant proportion of vasodilation.6 Similarly, NO activates platelet cGMP to reduce intraplatelet calcium concentrations, impairing platelet activation to a degree.7 In effect, nitrates act as exogenous NO donors, in addition to raising endogenous production of NO.8 Although the predominant effect of nitrates is to reduce preload, ie, produce venodilation, with greater activity in the venous than arterial beds, at higher doses its direct effect upon arteries is more pronounced, with a greater reduction in blood pressure (BP) and afterload. The net result is a reduction in myocardial oxygen consumption, but an overall increase in exercise capacity in patients with CAD as well, permitting a greater total workload before angina is triggered. In addition, NO improves endothelial function, which contributes to vasodilation and optimizes vascular reactivity.9,10 Finally, nitroglycerin redistributes coronary blood flow from normally perfused areas of myocardium to ischemic zones.11,12 A reduction in ventricular diastolic pressure and an increase in collateral blood flow play a part in this phenomenon, favoring subendocardial perfusion relative to the subepicardial. In an experimental model of coronary vasospasm, the observed rise in blood flow to the ischemic myocardium produced by nitroglycerin was not accompanied by diminished perfusion in normal myocardium
Prevalence and tracking of back pain from childhood to adolescence
Prevalence and characteristics of chronic musculoskeletal pain in Japan, 2011
Farnesyl pyrophosphate is a novel pain-producing molecule via specific activation of TRPV3. 2010
Farnesyl pyrophosphate synthesis is
- upregulated by thyroid hormones
- downregulated by statins
Candida, farnesol, Pain ??
Insulin and TRPV
Time course of pain sensation in rat models of insulin resistance, type 2 diabetes, and exogenous hyperinsulinaemia. 2008
Modulators of pain: bv8 and prokineticins. 2006
The Pain Institute
Pain negative modulator
T-type calcium channel inhibition underlies the analgesic effects of the endogenous lipoamino acids. 2009
In pazienti non ospedalizzati, la somministrazione endovenosa di ketamina può alleviare notevolmente il dolore cronico che caratterizza la sindrome dolorosa regionale complessa. Queste le evidenze di uno studio in doppio cieco e controllato con placebo pubblicato su Pain (2009;147:107-115). L'indagine, condotta dopo ottenimento del consenso informato dei pazienti, ha previsto attente valutazioni a partire da almeno due settimane prima del trattamento e per i tre mesi successivi...
On the basis of numerous data, it was suggested that GalR2 may mediate the hyperalgesic response in chronic pain, while GalR1 mediates the analgesic effect
ASMKO as a model
A pilot study of potassium supplementation in the treatment of hypokalemic patients with rheumatoid arthritis: a randomized, double-blinded, placebo-controlled trial. 2008
J Pain (2008) Show Abstract »
The elevated serum cortisol and potassium values in the treatment group correlate negatively with patient's assessment of pain intensity, reflecting an anti-pain effect for potassium supplementation.
Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain, 2011
Involvement of the melanocortin-1 receptor in acute pain and pain of inflammatory but not neuropathic origin. 2010
Response to painful stimuli is susceptible to genetic variation. Numerous loci have been identified which contribute to this variation, one of which, MC1R, is better known as a gene involved in mammalian hair colour. MC1R is a G protein-coupled receptor expressed in melanocytes and elsewhere and mice lacking MC1R have yellow hair, whilst humans with variant MC1R protein have red hair. Previous work has found differences in acute pain perception, and response to analgesia in mice and humans with mutations or variants in MC1R.
METHODOLOGY AND PRINCIPAL FINDINGS:
We have tested responses to noxious and non-noxious stimuli in mutant mice which lack MC1R, or which overexpress an endogenous antagonist of the receptor, as well as controls. We have also examined the response of these mice to inflammatory pain, assessing the hyperalgesia and allodynia associated with persistent inflammation, and their response to neuropathic pain. Finally we tested by a paired preference paradigm their aversion to oral administration of capsaicin, which activates the noxious heat receptor TRPV1. Female mice lacking MC1R showed increased tolerance to noxious heat and no alteration in their response to non-noxious mechanical stimuli. MC1R mutant females, and females overexpressing the endogenous MC1R antagonist, agouti signalling protein, had a reduced formalin-induced inflammatory pain response, and a delayed development of inflammation-induced hyperalgesia and allodynia. In addition they had a decreased aversion to capsaicin at moderate concentrations. Male mutant mice showed no difference from their respective controls. Mice of either sex did not show any effect of mutant genotype on neuropathic pain.
We demonstrate a sex-specific role for MC1R in acute noxious thermal responses and pain of inflammatory origin.