Experimental Study On The Analgesic Effects Of N-acetyl-5-Methoxytryptamine And Its Molecular Mechanisms

Objective and significance:Pain accompanies surgery, various diagnostic procedures and dental care as well as acute injury (or trauma) and many other diseases. It not only makes patients feel unbearably distressful and anxious,but also makes them fall into a serious stresss status, which secondarily resulting in functional disorders of many important organs. Under the condition of modern war especially, combined wounds and multiple injuries are more frequent, so that pain and its related complications will be more serious. Therefore, whether pain is in good control or not will obviously affect the outcome of rehabilitation of the patients. However, the analgesics used at the present for the treatment of severe pain (e.g pain in trauma), such as morphine and pethidine, can cause serious advise reactions, for example, respiratory suppression, increasing of intracranial pressure, postural hypotension, immunosuppression, addiction and so on. Hence, it is necessary to look for some new type of analgesic drugs, which have both good analgesic effects and no obvious side effects such as addiction and respiratory inhibition ,etc. N-acetyl-5-methoxytryptamine (also called melatonin, Mel) ,an endogenous active substance yielding from pineal gland, can be synthesized artificially nowadays. It was recently found that the Mel level in blood of many kinds of species including human beings shows a obvious day-night rhythm. It is noticeable that the basic pain thresholds in mice and the analgesic effects of morphine and pethidine (Pt) also shows the similar day-night rhythm, which nearly synchronizes with the known rhythm of Mel. It was reported that Mel levels in blood of patients with abdominal pain, cluster headache (CH), nerveous or impathetic painful disorder, and fibrouse myodynia were significantly decreased compared with that of healthy people. Some investigators used Mel to clinical trial in patients with CH and migraine and got some beneficial results. Besides, the fewer advise reactions and the immunoregulatory effects of Mel makes itself a promising candidate for new type of analgesic drugs with good analgesic effects and no obvious side effects. The study of central sensitization is an important topic in neuroscience. Based on thehypothesis of central sensitization, preemptive analgesia given before noxious stimulation has been proposed and become a new strategy of analgesia recently, which is recognized not only to help get a satisfactory analgesic effects, but also reduce the demands of analgesic drugs. However, the preemptive analgesic effects of Mel and a series of other questions about Mel such as the characteristics and the effects of Mel on severe(sharp) pain(trauma painful model), the synergistic action of Mel with Pt ( mostly used in clinical as a morphine substitute), and the dynamic changes of mu or kappa opioid receptor mRNA expression, central sensitization, mt1 and MT₂ receptor mRNA expression and the AANAT mRNA expression posttrauma, and the effects of Mel on these items are still unknown. The goal of the present study was to wholly evaluate the analgesic effects of Mel and explore its possible molecular mechanisms so as to provide new possibilities for the discovery of a new type of analgesic drugs and better control of pain patients. Materials and methods:A trauma-pain model was established in rats and the 55℃ hot plate model and acetic-induced writhing model were reproduced in rats in the present study. The non-specific opioid receptor antagonist naloxone and non-selective (mt1 and MT₂) Mel receptor antagonist luzindole were employed to understand the relationship between enogeneous opioid receptor, Mel receptor and the analgesic effects of Mel. The immunoreactivity of subtance P(SP) and Brain-derived neurotrophic factor (BDNF), and the expression of c-fos in spinal cord; the content of nitric oxide (NO), the expression of mu and kappa opioid receptor mRNA, mt1 and MT₂ receptor mRNA in spinal cord and brain tissues, and the expression of arylalkylamine N-acetyltransfe...