Opioid Receptors and Immune System - Essay Example

Opioid receptors and immune system Opioid drugs are commonly recommended around the world to cure severe to moderate pain. The analgesic agent opium,the original material extracted from opium poppy called Papaver somniferum is in use for millennia. The prototype opioid medicine morphine derived from opium is in use for around two hundred years and is used as the most effective opioid analgesic obtainable. The opioid medicines and their endogenous counterparts’ dynorphins, enkephalins and endorphins are agonists with opioid receptors. Opioid receptors take a crucial role in several pathological and physiological functions. The receptors are of significance for nociception, reinforcement of behavior and emotional behavior. The receptors are significant for the regulation of GI function, respiration and immune function. The receptors contribute an integral role based on the opioid drug used and also play a significant role based on other chemically unrelated medicines in the body. Opioid receptors are classified into mu, delta, kappa and NOP receptors (Gendelman, H.E. & Ikezu, T 2008 p.551) Kappa and delta opioid receptors affect various immune cells like peripheral blood polymorphonuclear leukocytes, lymphocytes and macrophages. On the other hand, KOP and DOP receptors are found in several immune cell types comprising B and T cells, macrophages, lymphocytes and pheripheral blood mononuclear cells. Kappa selective agonists and morphine increase KOP receptor symptom in human lymphocytic cell. The activation of T cells with anti-CD3-epsilon (CD3-e) paves way for increased symptoms of DOP receptors stimulating the cells for enhanced response to opioids either exogenous or endogenous. On using morphine to treat peripheral blood mononuclear cells, it promotes TH2 cell differentiation by increasing the production of IL-4. The analysis indicates that morphine suppresses the immune system. The outcome of the treatment is the failure of the cell induced immunity that has an important role in enhanced mortality and morbidity subsequent to a major surgery or trauma (Gendelman, H.E. & Ikezu, T 2008 p.553). Opioid agonists generate analgesia by associating with certain G protein coupled receptors in the spinal cord and brain region responsible for the modulation and transmission of pain. There are three major kinds of opioid receptors namely mu, kappa and delta found in several tissues and nervous system sites. The three receptors are now cloned and are known as members of G protein combined family of receptors that contain amino acid sequence homologies. There are multiple receptor subtypes proposed on the basis of pharmacologic criteria that comprise μ1, μ2; κ1, κ2, κ3 and δ1, δ2. Only one subtype from μ, κ and δ receptor group is isolated as per genes encoding. The plausible explanation indicates that the subtype μ receptor emerges from alternate splice modification of a common gene. There are possibilities that one opioid drug functions in association with various potencies as an antagonist, partial agonist or agonist at more than one subtype or class of receptor. This is the reason why the receptors have the capability to imply diverse pharmacologic outcomes. Opioid receptors combine to form a group of proteins at the molecular level that physically combines with G proteins. This interaction affects the ion channel gating, transform intracellular Ca2+ disposition and transforms protein phosphorylation. Opioids operate two established direct G protein combined action on neurons: They are (i) Opioids close voltage gated calcium channels on presynaptic terminals of the nerve and decreases transmitter release (ii) Opioids hyperpolarize and stop postsynaptic neurons with the opening of K channels. The presynaptic action results in the release of huge number of neurotransmitters comprising glutamate – a basic excitatory amino acid generated from nociceptive terminals of the nerve, together with norepinephrine, acetylcholine, substance P and serotonin. Most of the existing opioid analgesic functions basically as μ opioid receptor. Analgesia and the respiratory depressant, euphoriant and physical dependence factors of morphine are based on the actions of μ receptors. The μ receptor was basically described with the comparative potencies for clinical analgesia from a set of opioid alkaloids. The effect of opioid analgesic is complex and comprises interaction with κ and μ receptors (Katzung, B. G. 2007 p.492) The three main receptors are found in high intensity in the dorsal part of the spinal chord. Receptors are found in the primary afferents that transmit pain message, and in pain transmission neurons. Opioid agonists obstruct the movement of excitatory transmitters from primary afferents and directly stop the dorsal pain relaying neuron. Therefore, opioids cause a strong analgesic effect directly to the spinal cord (Katzung, B. G. 2007 p.493). The administration of opioid to manage post operative pain creates immune consequences in the patient. However, different opioids have varying effects. For example, tramadol and morphine exhibit varying effects on the function of the immune system. The change in the immune system of the body is assessed two hours after the intense administration of 100mg tramadol IM or 10 mg morphine IM. The analysis of natural killer cell activity and phytohemoagglutinin – stimulated T lymphocyte production reveals that phytohemagglutinin-stimulated lymphoproliferation is depressed by the stress caused during surgery. It may be noted that in patients administered with morphine, the production of lymph continued to be lesser than the base levels even after two hours of treatment. On the other side, in patients administered with tramadol, the production rate of lymph bounced back to its base levels. It is observed that natural killer cell activity is not considerably affected by the administration of morphine but tramadol enhances natural killer cell activity. In effect both morphine and tramadol reduces postoperative pain comparatively. The finding is that the administration of morphine and tramadol in analgesic doses stimulates different effects on the immune system. It has also been found that opioids cause adverse effect on the immune system of the body. Since surgical stress itself stimulates the dysfunction of the immune system the use of analgesic drugs further inhibits the function of the immune system. Tramadol is comparatively better than morphine because it induces a betterment of the postoperative immunosuppression and is more preferable to morphine while treating postoperative pain (Sacerdote et al. 2000 p:1411-1414). The opioid analgesic Fentanyl reacts mostly with the mu opioid receptor. Fentanyl registers its basic pharmacologic impact on the central nervous system. Sedation and analgesia are the therapeutic qualities of Fentanyl that increase tolerance for pain and reduce the awareness of suffering though there will be pain in the body. Fentanyl however causes depression to the cough reflex, respiratory centers and tightens the pupils. Opioid receptors combine with G-protein receptors to function both as negative and positive controller of synaptic transmission through G-proteins that stimulate effector proteins. Combining of the opiate induces the replacement of GTP for GDP in the G-protein molecule. Since cAMP and adenylate cyclase are the effector system present in the inner walls of the plasma membrane, the opioid reduces intracellular cAMP through the restriction of adenylate cyclasae. In continuation, the discharge of nociceptive neurotransmitters like GABA, substance P, acetylcholine, dopamine and noradrenaline is restricted. Opioids can also restrict the discharge of insulin, vasopressin, glucagons and somatostatin. The analgesic activity of Fentanyl is probably due to the transformation to morphine. The receptor open the calcium dependent inner rectification potassium channels (OP1 and OP3 receptor agonist) and close N-kind voltage activated calcium channels called OPC receptor agonist. The outcome of using Fentanyl is decreased neuronal exitability and hyperpolarization (Showing drug card for Fentanyl). The administration of Fentanyl to patients with faulty immune function reveals the effect of the opioid on the immune system. The intake of 3 microg/kg IV fentanly preliminary does through a two hour IV infusion containing 1.2 microg x kg(-1) x h(-1) and the blood test before and after the administration was tested for neutrophil antibody- dependent cell cytotoxicity, neutrophil phagocytic function, natural killer cell cytoxicity, T-lymphocyte production response, percent of lymphocyte population and antibody response in vivo. The administration of Fentanyl for a patient with faulty immune function resulted in significant and rapid increase in NKCC (natural killer cell cytotoxicity) with a coincident increase in the levels of CD8 (+) cells and CD16 (+) in the peripheral blood. However, Fentanyl did not impact other immune measurements. It is observed that Fentanyl does not suppress the resistance from immune system if there are no other coexisting diseases. Therefore the use of Fentanyl need not be restricted over the concern that it can suppress the functions of the immune system (Yeager at al. 2002 p:94-9). The opioids of morphine generate strong analgesia that is effective to treat pain and it produces several adverse effects on the immune system. Morphine reduces the efficiency of various adaptive and natural immunities and importantly decreases cellular immunity. The opioids in morphine results in the worsening of cancer and infection and leads to mortality and morbidity. It is also found that all opioids do not cause similar suppression of the immune system. Therefore, it is essential to evaluate the effect of each opioid before choosing an analgesic for treating pain. Buprenorphine is an opioid that is usually prescribed to treat chronic pain. Intense intracerebroventricular administration of the opioid does not cause adverse effect to the cellular immune system. The use of this opioid keeps the natural killer lymphocyte activity, lymph production, lymphocyte number and cytokine production unaffected. Comparatively, these immune markers are drastically reduced when the µ-agonist Fentanyl is used for treatment. The administration of morphine and buprenorphine reduced surgery related immunosuppression. It is observed that buprenorphine reverts NK lymphocyte activity to normalcy as prevailed during preoperative state. It may be concluded that the opioids of buprenorphine comprises more favorable features to be used as an analgesic without giving rise to immunosuppressive activity (Sacerdote, P 2006 p.9-15). Buprenorphine is prescribed to detoxify opioid, and for further maintenance therapy. Buprenorphine has high affinity for the mu receptor, antagonistic effects, analgesic potency when compared to morphine and has mild withdrawal symptoms (Seet et al. 2005 p:890-891). The administration of buprenorphine through injection does not change the T cell, NK cell and macrophage function while the use of morphine suppresses T cell and reduces the activity of natural killer cell cytotoxicity and reduces the T cell receptor, microphage activity comprising the reduction of nitric oxide, reduction of IL-2 and TNF-α production. Further buprenorphine is related to significant decrease of corticosterone (CSO) plasma levels and adrenocorticotropic hormone (ACTH) by not changing serotonin and norepinephrine levels. At the same morphine increases the levels of catecholamine and glucocorticoid. It is observed that buprenorphine does not induce the sympathetic nerve (SNS) function with bioamine proliferation or hypothalamic–pituitary–adrenal (HPA) center with glucocorticoid discharge and is not related to immuno suppression. Buprenorphine does impact the neuroendocrine system due to partial agonist properties and does not affect the functions of the immune system (Gomez-Flores, R & Weber, R.J. 2000 p.145-156). Reference Gendelman, H.E. & Ikezu, T (2008) Neuroimmune Pharmacology London: Springer Gomez-Flores, R & Weber, R.J. (2000) Differential effects of buprenorphine and morphine on immune and neuroendocrine functions following acute administration in the rat mesencephalon periaqueductal gray Journal of Immunopharmacology Vol:48, Iss.2 p.145-156 Available: http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T27-40WMS38-6&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=4b04c48e3e38611159dacbc028e9b519 Katzung, B. G. 2007 Basic & clinical pharmacology New York: McGraw-Hill Professional Sacerdote et al. (2000) The Effects of Tramadol and Morphine on Immune Responses and Pain After Surgery in Cancer Patients Anesthesia AnalgesiaVol: 90 p:1411-1414 Available: http://www.anesthesia-analgesia.org/cgi/content/abstract/90/6/1411. Accessed on June 11, 2009 Sacerdote, P (2006) Opioids and the immune system Palliative Medicine, Vol. 20, No. 8 p:9-15 Available: http://pmj.sagepub.com/cgi/content/refs/20/8_suppl/9 Accessed on June 14, 2009 Seet et al. (2005) Diffuse cystic leucoencephalopathy after buprenorphine injection Journal of Neurology, Neurosurgery, and Psychiatry Vol:76 p:890-891 Available: http://jnnp.bmj.com/cgi/content/extract/76/6/890 Accessed on June 11, 2009 Showing drug card for Fentanyl Available: http://www.drugbank.ca/drugs/DB00813 Accessed on June 11, 2009 Yeager et al. (2002) Intravenous fentanyl increases natural killer cell cytotoxicity and circulating CD16(+) lymphocytes in humans Anesthesia Analgesia Vol.94 Iss.1 p:94-9 Available: http://www.opioids.com/immune/fentanyl.html. Accessed on June 11, 2009 References and further reading may be available for this article. To view references and further reading you must purchase this article. Read More