Chronic pain, usually considered to be continuous or episodic pain of at least six months duration, is a common cause of major disability. Chronic pain involves affective, behavioural and social dimensions. The opioid system plays a major role in the pain controlling systems.
Objectives
Therefore, our main focus was to investigate the patients health status and differences in the expression of opioid receptors in skin and muscle tissues of chronic pain patients with fibromyalgia (FM), osteoarthritis (OA), psychosis (PS), rheumatoid arthritis (RA) and healthy controls (C).
Methods
The Visual Analogue Scale (VAS) and the Short Form 36-item (SF-36) Health Survey questionnaire were given to the patients. Snap frozen sections from skin and muscle tissues (taken from the left deltoid region) were obtained from 8 FM (all female, 30–65 years of age), 4 OA (2 females and 2 males aged 48–72 years), 5 female PS patients (aged 40–79 years), 3 RA (1 female and 2 males aged 48–72 years), and 9 age-matched healthy females (C). Total RNA was extracted, reverse transcribed, amplified and quantified by real time PCR (TaqMan, Perkin Elmer) using fluorogenic probes and specific primers for Delta (DOR), Kappa (KOR) and Mu opioid receptors (MOR). Intensity of expression in each tissue was determined. The expression of 18S mRNA was used as an internal control.
Results
We observed a significantly reduced score in all patient groups compared to the control group regarding physical function in the SF-36 as well as in the VAS. An increase of DOR mRNA expression was found in PS and RA muscle, a decrease of KOR mRNA expression could be detected in OA skin compared to C. An increased expression of DOR (81.0 fold p = 0.001) and of KOR (13.6 fold p = 0.009) mRNA was detected in FM skin compared to skin of healthy controls. This expression was more increased in FM than any other investigated chronic pain condition. MOR was detected only in one skin and one muscle sample of two different PS patients.
Conclusion
Patients expressing high levels of DOR and KOR including patients with FM, PS, and RA might be treated with novel therapeutic approaches modulating opioid receptors expression by selective opioids. Dr. Salemi was supported by the Zurzach foundation and Dr. Sprott by the AFSA and the Olga Mayenfisch foundation.
The treatment of verapamil toxicity was examined in lightly sedated dogs. Verapamil, administered as a bolus (0.72 mg/kg) followed by a continuous infusion (0.11 mg/kg per min), decreased cardiac output (CO) from 3.1 +/- 0.1 to 1.7 +/- 0.1 liter/min (P less than 0.001), heart rate (HR) from 85 +/- 4 to 57 +/- 3 beats/min (P less than 0.001), left ventricular derivative of pressure with respect to time (LV dP/dt) from 2,085 +/- 828 to 783 +/- 78 mm Hg/s (P less than 0.001), mean aortic pressure (AO) from 77 +/- 4 to 38 +/- 2 mm Hg (P less than 0.001) and stroke volume from 39 +/- 3 to 28 +/- 2 ml/beat (P less than 0.01). In verapamil-toxic animals isoproterenol increased HR, CO, LV dP/dt, and AO; calcium chloride increased LV dP/dt and AO; norepinephrine, epinephrine, and dopamine increased CO, AO, and LV dP/dt, atropine increased HR, CO, and AO. Phenylephrine (13-55 micrograms/kg per min) produced no changes except a small increase in AO while very high dose phenylephrine (300 micrograms/kg per min) increased AO, CO, and LV dP/dt. 4-Aminopyridine (4-AP) increased HR, CO, LV dP/dt, and AO. When administered prior to verapamil, 4-AP prevented the development of verapamil toxicity as shown by the significantly higher AO (P less than 0.001), CO (P less than 0.01), and LV dP/dt (P less than 0.01) when 4-AP followed by verapamil was compared to verapamil alone. In conclusion, there does not appear to be a single specific therapy for verapamil toxicity, however it can be partially corrected by presently available pharmacologic therapy and 4-AP.
Apoptosis is a principal mechanism in metazoans by which superfluous or potentially harmful cells are eliminated.Deregulation of this process leads to a variety of diseases such as cancer and autoimmune diseases.Stimuli that can induce apoptosis are relatively diverse, and include the death factors (Fas ligand, tumor necrosis factor and TRAIL), DNA damage, and oxidative stress.Regardless of the origin of the apoptotic stimulus, commitment to apoptosis leads to activation of caspases, a family of cysteine proteases.Cleavage of a select group of cellular substrates by caspases is responsible for the morphological and biochemical changes that characterize apoptotic cell death.The degradation of nuclear DNA into nucleosomal units is one of the features of apoptotic cell death, and is mediated by a caspase-activated DNase (CAD).Cells deficient in CAD undergo cell death without the DNA fragmentation, but CAD-null mice did not show any adverse phenotypes.A close examination of the apoptotic cells in these mice indicated that apoptotic cells are always in macrophages.It seems that at an early stage of apoptosis, the dying cells present an 'eat me signal' on their surface.This signal is recognized by macrophages for engulfment, and DNase II in the lysosomes of macrophages degrades DNA of apoptotic cells.Mice deficient in both CAD and DNase II genes were established, and the development of various organs was found to be severely impaired in these mutant mice.The mice accumulated a large amount of undigested DNA in macrophages in various tissues during development.This accumulation of DNA in macrophages activated the innate immunity to induce the expression of the interferon β gene.The interferon thus produced seems to be responsible for the impaired tissue development.These results indicate that the degradation of DNA during apoptotic cell death is an essential step of apoptosis to maintain mammalian homeostasis.
