Effects of Opiates

A common strategy for treating chronic opiate addiction iavolves the substitution of methadone which can either be provided as maintenance therapy or tapered until abstinence is achieved. Naltrexone and buprenorphine [52485-79-7] have also been used ia this manner. The a2 adrenergic agonist clonidine [4205-90-7] provides some rehef from the symptoms of opiate withdrawal, probably the result of its mimicking the inhibitory effect of opiates on the activity of locus coerukus neurons. 

The pharmacological and/or adverse effects of a drug can be reversed by co-administration of drugs which compete for the same receptor. For example, an opioid receptor antagonist naloxone is used to reverse the effects of opiates. Drugs acting at the same site with opposite effects also can affect each other, e.g. the reduction in the anticoagulant effect of warfarin by vitamin K. 

The locus cemleus is important for the regulation of attentional states and autonomic nervous system activity. It has also been implicated in the autonomic and stress-like effects of opiate withdrawal. A noradrenergic pathway originating from the locus cemleus which descends into the spinal cord is part of the descending inhibitory control system, which has an inhibitory effect on nociceptive transmission in the dorsal horn. 

Ledent C, Valverde L, Cossu G, et al Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CBl receptor knockout mice. Science 283 401-404, 1999... 

The large numbers of opioid receptors in areas of the brainstem such as the solitary tract and adjacent areas are probably related to respiratory effects of opiates, cough suppression and nausea and vomiting. Opiates acting in the brainstem reduce the sensitivity of the respiratory centres to pC02 and this is the most common cause of death from overdose with street use of opiates. 

Opiates activate the chemoreceptor trigger zone in the medulla (by disinhibition) to cause nausea and vomiting, and cough suppression also occurs because of the inhibitory effects of opiates on the brainstem nuclei in the cough reflex pathway. Dextromethorphan is the non-opiate isomer of the opiate levorphanol and is an effective cough suppressant. 

There are a number of side-effects of opiates that are due to their actions on opiate receptors outside the central nervous system. Opiates constrict the pupils by acting on the oculomotor nucleus and cause constipation by activating a maintained contraction of the smooth muscle of the gut which reduces motility. This diminished propulsion coupled with opiates reducing secretion in the gut underlie the anti-diarrhoeal effect. Opiates contract sphincters throughout the gastrointestinal tract. Although these effects are predominantly peripheral in origin there are central contributions as well. Morphine can also release histamine from mast cells and this can produce irritation and broncho-spasm in extreme cases. Opiates have minimal cardiovascular effects at therapeutic doses. 

Codeine, hydrocodone, morphine, methadone, and oxycodone are substrates of the cytochrome P-450 isoenzyme CYP2D6.47 Inhibition of CYP2D6 results in decreased analgesia of codeine and hydrocodone due to decreased conversion to the active metabolites (e.g., morphine and hydromorphone, respectively) and increased effects of morphine, methadone, and oxycodone. Methadone is also a substrate of CYP3A4, and its metabolism is increased by phenytoin and decreased by cimetidine. CNS depressants may potentiate the sedative effects of opiates. 

When Montgomery and I published our article, we thought we had disproven another theory of placebo effects - the theory that placebo effects are produced by the release of endorphins in the brain. In 1978 researchers at the University of California in San Francisco discovered that when placebos reduce pain, they may stimulate the release of endorphins.18 Endorphins, the existence of which had only been discovered a few years earlier, are opioids that are produced naturally by the brain. Just like the opiates that are derived from opium - morphine and codeine, for example - endorphins reduce the sensation of pain. The University of California researchers reasoned that if placebos can mimic the effects of opiate drugs, maybe they do so by stimulating the release of the brain s endogenous opioids. 

Acute physiological responses to opiate administration occur rapidly and include constricted pupils, decreased pulse rate, reduced body temperature, slowed respiration rate and impaired reflexes. In addition, there is a marked slowing of the digestive system through an altering of the tonus and motility of the stomach and intestines, allowing for greater water absorption. This last effect is not subject to tolerance, and constipation is a common side effect even for chronic users. Indeed, some report that this is the worst side effect of opiate use. 

Animation showing the effects of opiates on dopamine www.wnet.org/closetohome/animation/opi-anim-main.html... 

The reinforcing effects of opiate drugs involve a number of neuronal pathways [21]. In the VTA, opiates stimulate p-opioid receptors on GABA neurons that synapse on dopamine neurons. This inhibits the GABA neurons, leading to disinhibition of the dopamine neurons and enhanced dopamine release in the nucleus accumbens and other target areas (Fig. 56-3). Opiates also exert dopamine-independent effects in the nucleus accumbens by activating... 

Chronic opiate treatment results in complex adaptations in opioid receptor signaling. Much has been learned from studies on mechanisms of tolerance to the analgesic effects of opiates. This is a major clinical problem, as it means that ever-escalating doses are required for the treatment of chronic pain. The classic view was that tolerance reflects a decrease in functional opioid receptors via desensitization and internalization. Desensitization occurs when receptors are uncoupled from G proteins as a result of phosphorylation by G-protein-coupled receptor... 

There are two main treatments for the opiate withdrawal syndrome. One is replacement therapy with methadone or other X agonists that have a longer half-life than heroin or morphine, and produce mild stimulation rather than euphoria. They also produce cross-tolerance to heroin, lessening heroin s effect if patients relapse. Withdrawal is also treated with the 0C2 agonist clonidine, which inhibits LC neurons, thus counteracting autonomic effects of opiate withdrawal — such as nausea, vomiting, cramps, sweating, tachycardia and hypertension — that are due in part to loss of opiate inhibition of LC neurons. 

Sacerdote, P. et al., Antinociceptive and immunosuppressive effects of opiate drugs A structure-related activity study, Hr. J. Pharmacol., 121, no. 4, 834—840, 1997. 

The common side effects of naltrexone are nansea, headache, and dizziness. In addition, naltrexone has the potential for toxic effects on the liver and should not be used in an alcoholic with cirrhosis or other known liver disease. Because it blocks opiate receptors, patients treated with naltrexone are unable to benefit from the analgesic effects of opiates such as codeine or morphine. Naltrexone may increase serum levels of acamprosate in patients taking both medications. 

F8. Foulk, W. T., and Fleisher, G. A., The effect of opiates on the activity of serum transaminase. Proc. Staff Meet. Mayo Clin. 22, 405-410 (1957). 

There are some clinically important pharmacodynamic drug-drug interactions to be mentioned. Antipsychotics will potentiate the central depressant effects of sedatives and of alcohol. They will also increase the risk of respiratory-depressant effects of opiates. Inducers of drug metabolic enzymes like for example rifampicin and several antiepileptics, may increase the elimination rate of antipsychotic agents and thus decrease their efficacy. 

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. 

Antagonism Reversal of the effect of opiates with naloxone. 

Bardo, Michael T., Janet L Neisewander, and Robert C. Pierce. 1989. "Novelty-Induced Place Preference Behavior in Rats Effects of Opiate and Dopaminergic Drugs." Pharmacology Biochemistry and Behavior 32 683-69. 

Koob, George F., Tamara L. Wall, and Floyd E. Bloom. 1989b. "Nucleus Ac-cumbens as a Substrate for the Aversive Effects of Opiate Withdrawal." Psychopharmacology 98 530-34. 

Mucha, Ronald F. 1987. Is the Motivational Effect of Opiate Withdrawal Reflected by Common Somatic Indices of Precipitated Withdrawal A Place-Conditioning Study in the Rat." Brain Research 418 214-20. 

S tin us, Louis, Michel Le Moal, and George F. Koob. 1990. "Nucleus Accumbens and Amygdala Are Possible Substrates for the Aversive Stimulus Effects of Opiate Withdrawal." Neuroscience 37 767-73. 

Naloxone will block the effects of opiate drugs and is used to treat overdoses. It was found that during trauma the use of naloxone would increase pain and prevent naturally induced analgesia. It was only a matter of time until the endogenous opiates, the endorphins (for endogenous morphine) and enkephalins, were discovered. Now there exists a whole nomenclature of opiate receptor types and their various effects. 

Researchers discover that special receptors in the brain are responsible for the effects of opiates. This discovery paves the way for research into ways to block these effects. 

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