Production, of opiates

If we are to harness the placebo effect and make use of it in clinical practice, we first have to understand how it works. A number of factors have been proposed as explanations of the placebo effect. These include the relationship between doctors and patients, the patient s beliefs and expectations, the production of opiates in the brain, and a phenomenon called classical conditioning, in which people come to associate pills and injections with therapeutic effects, just as Pavlov s dogs came to associate the sound of a bell with the presentation of food. In this chapter we look at how all of these processes combine to produce placebo effects, and we consider their implications for the treatment of depression. 

We are indepted to Dr. Hans H. Bosman for data on the production of opiates and Dr. Joannes T.M. Linders for some useful suggestions. 

Table 2 Worldwide production of opiates in tons (numbers in brackets represent production in the US) (see footnote 1)...

Other constraints are important for more complex products, for which mass is not central, but value. For example, central nervous system stimulants are a new class of substances addressed by production with engineered baker s yeast. Expressing the biosynthetic pathways for the opioids thebaine and hydrocodone, and parts of the morphine pathway in yeast, a first step is taken for easy production of opiates [21, 22]. This opens the possibility for the development of new painldllers with less addictive potential. However, it clearly is a new technology that could be abused with many negative consequences - so some contemplation about how to control these developments seems advisable [23]. Not only are narcotics in the center of interest but stimulants such as caffeine and theobromine have also recently been produced with genetically engineered 5. cerevisiae strains [24]. 

The Opiates. The International Narcotics Control Board—Vienna, tracks the tick production of narcotic dmgs and annually estimates world requkements for the United Nations. Thek most recent pubHcation (100) points out that more than 95% of the opium for Hcit medical and scientific purposes is produced by India and, in a declining trend, only about 600 t was utilized in 1988. This trend appears to be due to the fact that the United States, the largest user of opium for alkaloid extraction, reduced the amount of opium being imported from about 440 t in 1986 to 249 t in 1987 and 224 t in 1988. The United States used about 48 t of morphine (2, R = H) in 1988, most (about 90%) being converted to codeine (2, R = CH3) and the remainder being used for oral adrninistration to the terminally ill (about 2 t) and for conversion to other materials of minor commercial import which, while clearly alkaloid-derived, are not naturally occurring. 

French CE et al. (1995) Biological production of semisynthetic opiates using genetically engineered bacteria. Biotechnology (NY) 13(7) 674-676... 

FIGURE 1 8-5 Tissue-specific processing of the pro-opiomelanocortin (POMC) precursor yields a wide array of bioactive peptide products. Processing of the POMC precursor varies in various tissues. In anterior pituitary, adrenocorticotropic hormone (ACTH (1-39)) and P-1 ipo tropin (P-LPH) are the primary products of post-translational processing. Arcuate neurons produce the potent opiate P-endorphin (P-endo (1-31)) as well as ACTIK1 -13) NIT,. Intermediate pituitary produces a-melanocyte-stimulating hormone (aMSH), acetylated P endof 1 31) and P-endo(l-27). NTS, nucleus tractus solitarius. 

An example in point is Johnson Matthey, the world s largest supplier of opiates. The products are obtained by plant extraction, which is the company s core competence. JM acquired the chemical CRO PharmEco with the intent to offer a one-stop shop capability. As PharmEco was primarily involved in synthetic chemistry, it is difficult to come across a synergy between the small- and the large-scale business. 

Since they are linked to G-proteins, opioid receptors affect intracellular Ca and protein phosphorylation. Another principal biochemical effect of opiates is the inhibition of adenylate cyclase (AC), which decreases cAMP production. 

Between 2002 and 2005, the proportion of opiate seizures along the Afghanistan-Europe trafficking route increased from 78 to 87 per cent, reflecting rising opium production in Afghanistan. Seizures along the other two main routes decreased, from 15 to 10 per cent for South-East Asia/Oceania and from 7 to 4 per cent from Latin America to North America. These reflect production declines in South-East Asia and Latin America. 

Most countries of East and South-East Asia reported declines in opiate abuse in 2005, reflecting the strong declines of opium production in Myanmar and Lao PDR. The Chinese market was reported to have been stable, as declining levels of opiates from Myanmar were offset by a rising opiate supply from Afghanistan. From 1992 to 2005, the drug use perception indicator for... 

In the United States, the Harrison Narcotics Act of 1914 provided the first real regulation of the general sale of opiates. The exceptions were sales to licensed physicians for use on their own patients, and sales to those people who could provide a written prescription from a doctor. The adoption of laws controlling the production and distribution of all prescription medications occurred primarily because of morphine and codeine. 

Methadone and opiates were first used for pain relief, and are still chiefly used in that area of medicine. It is important to remember that methadone and other opiates do not exert their pain control by altering a person s sensitivity to pain. Rather, methadone and other opiates interfere with the transmission of pain impulses from the nervous system to the brain. They accomplish this by a variety of methods. First, they decrease the transmission of nerve signals that conduct pain messages from various parts of the body to the spine. Secondly, they prevent production of neurochemicals that transfer this pain information to the spine. Finally, they mimic the actions of endorphins, which are the body s own pain-controlling chemicals. While methadone and other opiates work quite well to control pain, they do not affect touch, vision, or hearing. 

The term opiate describes the class of molecules structurally and pharmacologically related to morphine, the main alkaloid of opium, which is a product of Papaver somniferum, a plant illegally cultivated in Asia, whose effects have been recognized since 4000bc by the Sumers. 

Data on bioactivity on immunocompetent cells provide evidence that D-Ala-deltorphin-I potently (10-9 to 10-11 M) and persistently (up to 4 days) enhances Con A-induced mouse spleen cell proliferation [85]. The peptide increases uptake of thymidine and production of interferon--/ in phytohe-magglutinin-activated human lymphocytes [86] and is 100 times more potent than SNC80 in inhibiting the production of p24 antigen, an index of HIV-1 expression, in Jurkat cells stably transfected with a cDNA encoding for the delta-opiate receptor [87]. 

Cannabinoids may share at least some common neuronal mechanisms with opioid compounds. Studies of intracellular events associated with ligand binding to either cannabinoid or opiate receptors indicate that these receptors are linked via G proteins to the production of cAMP. Certain studies have also indicated that there may be some interaction between cannabinoid binding sites and opiate receptors in the reward pathway. In addition, there is increasing evidence that cannabinoids interact with opiate systems involved in the perception of pain. In fact, cannabinoids clearly produce analgesic effects in both experimental animals and humans, and of all the potential clinical uses of cannabinoids, the mediation of analgesia has received the most attention. Some evidence also indicates that the cannabinoid receptor system is an analgesic system. 

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