Novel Molecular Factors in the Pathochemical Mechanisms Supporting Chronic Back Pain?


Igor G.Bondarenko, MD, PhD; Juhani Tevren, DC; Rainer Boeger, MD, Prof.; Jukka Chydenius,DC
Recurrent character of the chronic back pain often indicates that there are endogenous chemical mechanisms sustaining the local aseptic (non-microbial) inflammation in the connective tissue and, therefore, pain. The mechanism that has been described best is an overproduction of the mediators of inflammation in the tissues such as prostaglandins and leukotrienes. Pharmacological approach to the correction of that pathophysiological process is the use of non-steroidal anti-inflammatory drugs (“pain-killers”) supposed to inhibit cyclooxygenase and lipoxygenase, the enzymes catalysing the synthesis of the aforementioned pro-inflammatory chemicals. There exists a different cohort of endogenous substances in the body which, although not behaving as direct inducers of the pain by acting on the nociceptors in the damaged area, may impair the structural integrity of the major proteins of connective tissue – collagen(s) and elastin. Homocysteine, a sulfur-containing amino acid, has been equivocally claimed to be associated with the higher risk of cardiovascular conditions. Hyperhomocysteinemia has been proven to be an independent risk factor of cardiovascular disease, including atherosclerosis and stroke, and is connected to insulin resistance. There is also a link between elevated levels of homocysteine and neurodegenerative diseases. Evidence exists that homocysteine-induced damage to the vascular wall is due to the impairment in the structure of its collagen and elastin, both by the inhibition of the assembly/maturation of those proteins. Destructive effects of homocysteine are not restricted by vascular wall only. Hyperhomocysteinemia has been shown to be associated with the increased risk of hip fracture in the elderly. As early as in 1976, experiments by Griffiths et al. demonstrated that excess homocysteine can decrease the level of cross-linking of the collagen in the tendons, thus making collagen mechanically weaker. Twenty years later, Liu G. et al. (1997) confirmed the irreversible inhibition of lysyl oxidase, the enzyme responsible for strengthening collagen and elastin by cross-linking their filamentous chains, by homocysteine thiolactone – the product of homocysteine breakdown in the body. A single-point mutation in the gene leading to the elevation of homocysteine has been proven to be associated even with the decrease of bone mineral density. Another endogenous chemical potentially involved in the labilisation of the major proteins of connective tissue is NG, NG-asymmetrical dimethylarginine (ADMA). This methylated derivative of the amino acid arginine, described by P. Vallance et al. (1992), is synthesised in the body from it own proteins and acts as a specific inhibitor of nitric oxide synthase family, therefore diminishing the production of nitric oxide in the tissues. Similar to homocysteine, elevation of ADMA level is associated with the increased risk of cardiovascular conditions – it has been reported in hypercholesterolaemia, peripheral arterial occlusive disease, hypertension, chronic heart failure, and coronary artery disease, as well as in diabetes mellitus. Moreover, higher values of ADMA in blood have been diagnosed in patients with hyperhomocysteinemia, which emphasises the pathophysiological proximity and interrelations between homocysteine and ADMA in the pathogenesis of cardiovascular diseases. Again, as in the case of homocysteine, it seemed plausible to suggest that the effects of ADMA on blood vessel wall could be, in particular, accounted for by its damaging action on the connective tissue proteins. In that case, the association between the elevation of ADMA and the possible impairment of collagen and/or elastin could result to other clinical conditions, in which structural integrity of collagen/elastin plays a primary role. Very few disperse data indirectly support the suggestion. Experimental studies by Lu R. et al. (2002) have demonstrated that age-related decrease in bone mineral density in the spine, tibias and femora correlated with the increase of serum levels of ADMA. In particular, it could be accounted for by the inhibition of osteoblastic differentiation by ADMA. In clinical studies, almost two-fold elevation of ADMA levels in the cerebrospinal fluid of the patients with lumbar spinal canal stenosis has been demonstrated. In our preliminary study, levels of ADMA (analysed by high-performance liquid chromatography) in the blood serum of 10 patients (male: 8, female: 2, age: 31-69) with chronic back pain were found to be close to the upper reference limit (“upper normal value”) or to exceed it. If the hypothesis on the role of endogenous destabilisers of major connective tissue proteins in the mechanisms of chronic pain is supported in further studies, a specific nutritional supplementation can be developed to reduce the levels of ADMA and/or homocysteine in the body fluids and, therefore, to augment the efficiency of chiropractic treatment of chronic back pain.