Brain delta receptor sites

If opiates are such addictive and potentially lethal compounds, why does the body respond to them As with the cannabinoids (Chapter 7), it has been discovered that the body and brain possess numerous opiate-specific receptor sites. As many as nine receptor subtypes have been identified, with three of them being the most important p (mu), k (kappa) and 8 (delta). The finding that the distribution of opiate receptors did not parallel the distribution of any known neurotransmitter prompted the search for and identification of a number of endogenous compounds specific to these receptors. These enkephalins and endorphins are manufactured within the brain and other body systems (especially the gut and intestines) and form the body s natural response to pain. They appear to be produced in bulk chains of amino acids called polypeptides , with each active neurotransmitter being composed of around five amino acid molecules. These active neurotransmitters are subsequently cleaved from the larger polypeptides at times of demand for example, it has been demonstrated that the plasma levels of these active compounds rise during childbirth, traumatic incidents and vigorous physical exercise. 

Scientific research has shown that methadone and other opiates have specific areas, or sites, that they attach to in order to exert their influence on the brain and body. These sites, called receptors, are classified as mu, delta, and kappa, depending on what body functions they influence. Opiate activation of mu and delta receptors seems to influence mood, respiration, pain, blood pressure, and gastrointestinal functions. Kappa receptors appear to be more involved in the perception and aversion to pain. The degree of methadone s effect on these receptors can vary widely between individuals, however, there are certain effects that are almost universal. 

All opioids produce their effect by activating one or more of the three types of receptors. Thus analgesia involves the activation of the mu receptors that are located mainly at supraspinal sites and kappa receptors in the spinal cord delta receptors may also be involved but their relative contribution is unclear. Nevertheless, the actions of the opioids on these receptors is complex, as there is evidence that the same substance may act as a full agonist, or as an antagonist at different sites within the brain. 

The delta receptor was the first opioid receptor to be cloned in 1992, almost 20 years after opioid binding sites were discovered in the brain [1,2]. Cloning was achieved simultaneously by two independent teams, using an expression strategy [3,4]. Homology cloning techniques then delivered the whole opioid... 

When the efficacy of biphalin-stimulated G protein activation was examined (Table 3) in delta opioid receptor-transfected CHO cells, an efficacy ratio of 0.42 was determined as compared with deltorphin-II and DPDPE, the latter a reference delta-selective agonist. Such low efficacy values suggest that biphalin does not efficiently stimulate the G protein through the delta receptor [9]. Relative affinities of biphalin and morphine for mu, delta, and kappa binding sites in guinea pig brain membranes are shown in Table 4. 

Xu H, Partilla JS, de Costa BR, Rice KC, Rothman RB. Differential binding of opioid peptides and other drugs to two subtypes of opioid deltancx binding sites in mouse brain further evidence for delta receptor heterogeneity. Peptides 1993 14 893-907. 

Heroin s primary toxic principle is its profound ability to depress the central nervous system (CNS). Opioid analgesics bind with stereospecific receptors at many sites within the CNS. Heroin, similar to other opioids, exerts its pharmacologic effect by acting at mu, kappa, and delta receptors in the brain. Although the precise sites and mechanisms of action have not been fully determined, alterations in the release of various neurotransmitters from afferent nerves sensitive to painful stimuli may be partially responsible for the analgesic effect. Activities associated with the stimulation of opiate receptors are analgesia, euphoria, respiratory depression, miosis, and reduced gastrointestinal motility. 

Endogenous opioid peptides (endorphins, dynor-phins, enkephalins), have been termed the brain s own morphine. Their discovery in 1972 explained why the brain has opioid receptors when there were no opioids in the body. These peptides attach to specific opioid receptors, mainly p (mu), 5 (delta) or K (kappa) located at several spinal and multiple supraspinal sites in the CNS. Opioid receptors are part of the family of G-protein-coupled receptors (see p. 91) and act to open potassium channels and prevent the opening of voltage-gated calcium channels which reduces neuronal excitability and inhibits the release of pain neurotransmitters, including substance P. 

---