Addiction, opiate receptor system

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. 

Use of the opium poppy (Papaver somniferum) to ameliorate pain dates back thousands of years, and the active metabolite morphine (2) was isolated first from its extracts in 1806 followed by codeine (53) in 1832 (27, 28). Morphine and its derivatives are agonists of opiate receptors in the central nervous system and are some of the most effective pain relievers known and prescribed for postoperative pain. Morphine and codeine differ by substitution by methyl ether. Unfortunately, addictive properties of these compounds limit their use. Efforts have been made to reduce the addictive properties of morphine, which resulted in a semisynthetic derivative buprenorphine (54) (29). This compound is 25 to 50 times more potent than morphine with lower addictive potential and has been indicated for use by morphine addicts. 

Physical addiction is receptor-mediated. Opiates exhibit tolerance, so a progressive increase in dose must be maintained over time in order to continue to achieve desired effects. This effect is manifested by a decrease in receptor number and sensitivity. Upon withdrawal, the receptor number and relative sensitivity to endogenous opiates is insufficient for normal bodily function. In addition, opiates affect all organ systems, particularly the heart and skeletal muscle. Abrupt withdrawal may precipitate convulsions and cardiovascular/cardiopulmonary abnormalities, particularly as a result of altered levels of norepinephrine. Gastrointestinal disturbances may also be manifested, and, because nociceptive levels are also affected, hyperalgesia may also result. 

The endogenous endorphin system is involved in cocaine addiction as well. Cocaine addiction causes an increase in the number of the brain s opiate receptors, thought to be a response to a decrease in release of endogenous endorphins. 

Antagonist potencies measured in vitro in the guinea pig ileum system or in vivo by extent of withdrawal in addicted animals should closely parallel the affinity of opiates for the receptor site. Both antagonist potencies and stero-specific binding constants have been measured for a number of N-substituted 5,9 dimethyl 2 hydroxy 6,7 benzomorphan analogues (14, 15, 32). Table III gives these values for the compounds studied and shows the extent of correlation between the known affinities and potencies for four analogues. 

Sdentitic studies of opioid neurotransmitters during the 1970s have uncovered a complex and subtle system that exhibited impressive diversity in terms of endogenous ligands for only three major receptors. The opioid peptide precursors were subject to complex post-translational modifications resulting in the synthesis of multiple active peptides all of them sharing the common N-terminal sequence of Tyr-Gly-Gly-Phe-(Met or Leu), which has been termed the opioid motif. Based on the results of theses studies, the endogenous opioids have been implicated in circuits involved in the control of sensation, emotion, and affect and a role has been ascribed to them in addiction, not only to opiates such as morphine or heroin, but also to alcohol. ... 

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