Neuropeptides, agonists and antagonists
One finds in the brain, and generally also in the digestive tract, peptides which play the role of transmitters or neuromodulators such as enkephalins, nociceptin, substance P, and neurotensin and are called neuropeptides.
Morphine properties (analgesia, tolerance, dependance) have been known for a very long time. The discovery of morphine receptors was based on the finding in brain extracts of macromolecules binding morphine in a stereospecific, saturable and competitive way.
The endogenous agonists of morphine receptors, discovered later in the brain, are polypeptides called endogenous opioids. They derive by complex cleavages from three precursors, pro-opiomelanocortine, proenkephaline and prodynorphine. Opioids consisting of 15 to 30 amino acids are called endorphins, those consisting of less than 10 amino acids are called enkephalins, the principal ones being Leu-enkephalin and Meth-enkephalin. Macrophages and lymphocytes also synthesize enkephalins, particularly during inflammation. They are inactivated by enkephalinases and the inhibitors of enkephalinases induce an increase in their tissue concentration. Other endogenous peptides, such as the tetrapeptides endomorphine-1 and endomorphine-2 whose precursors have not yet been identified have a high affinity for mu receptors, which they activate eliciting analgesia.
There are central and peripheral opioid receptors but divergences remain concerning their subtype classification. The best known are mu and kappa receptors . The activation of mu receptors induces analgesia, respiratory depression, constipation, dependance, miosis, hypothermia. The activation of kappa receptors, elicits analgesia, sedation, miosis and perhaps dysphoric reactions. D elta-opioid receptors are present particularly in the spinal cord; their activation induces an analgesic effect. Analgesia can result from activation of mu, kappa and delta receptors and dependence mainly from mu receptor activation. Opioid receptors are coupled to G proteins. Sigma receptors, initially thought to be a type of opioid receptors and later phencyclidine NMDA receptors are now considered as separate receptors.
Enkephalins also stimulate receptors located on peripheral neurons, which take part in their analgesic effect. The development of enkephalinomimetic drugs active without penetrating into the brain is possible.
The presence of endogenous peptides in the brain having algesic effects, i.e. opposed to that of morphine and endogenous opioids, sometimes called anti-opioids, shows the complexity of the regulation of pain perception. One of these endogenous peptides consisting of 17 amino acids, nociceptin also called orphanin FQ, activates a receptor called ORL-1 (opioid receptor like-1). Its antagonists could be likely to reduce pain intensity.
These considerations underline the extreme complexity of the various peptides as well as their receptors. In this chapter, we will describe the main properties of opioid agonists and the antagonists in human beings without classifying them according to the specific receptors which they activate.