Opiate action effects

Administration of naloxone prevents or reverses the effects of the opiates. The exact mechanism of action is not fully understood, but it is believed that naloxone reverses opioid effects by competing for opiate receptor sites (see Chap. 19). If the individual has taken or received an opiate, the effects of the opiate are reversed. 

Numerous possible mechanisms of action at the biochemical level have been proposed, in order to explain the effects of opiates. In recent years the possibility that Ca + disposition is an important underlying site of opiate action has attracted widespread interest. This is particularly so in view of the fact that Ca + is involved in numerous aspects of neuronal function, a number of which are also known to be affected by opiates, and in particular, neurotransmitter release. The concept that Ca + represents a general site of opiate action has therefore arisen as a possible explanation for the varied behavioral and biochemical effects of these drugs. 

The reports of Ca + involvement in opiate actions have lead to numerous examinations of narcotic effects on Ca +... 

The cited literature indicates that there is much evidence in favor of the suggestion that opiate drug effects involve Ca + disposition in some way. However, the multiple, and mutually interdependent actions of Ca + in neuronal function make it difficult to establish at which sub-cellular site or sites significant opiate-Ca + interactions are occurring. 

This is especially true since a number of Ca2+-dependent effects are known to be susceptible to opiate action. The picture is further complicated by the possibility that in some cases opiate effects may not involve Ca +, while in the instances where opiate-Ca + interactions can be demonstrated, the effects on Ca + may be either directly related to drug action or may be the indirect consequence of other opiate actions such as effects on body temperature, pH or oxygen tension. 

Alternatively, it may be argued that the opiate induced changes in Ca + flux, may be secondary to altered neuronal activity caused by other more important opiate actions which do not directly involve Ca + metabolism. Similarly, it may be that while Ca + has often been observed to antagonize opiate effects, this only indicates that the Ca + can alter levels of neuronal activity but does not prove a direct effect of opiates on Ca + Since these two differing interpretations may be placed on much of the data, it would seem that an important objective for future work in this field is to instigate research which will effectively demonstrate whether or not opiate effects are being produced as a direct consequence of drug effects on Ca +. 

P-Endorphin. A peptide corresponding to the 31 C-terminal amino acids of P-LPH was first discovered in camel pituitary tissue (10). This substance is P-endorphin, which exerts a potent analgesic effect by binding to cell surface receptors in the central nervous system. The sequence of P-endorphin is well conserved across species for the first 25 N-terminal amino acids. Opiates derived from plant sources, eg, heroin, morphine, opium, etc, exert their actions by interacting with the P-endorphin receptor. On a molar basis, this peptide has approximately five times the potency of morphine. Both P-endorphin and ACTH ate cosecreted from the pituitary gland. Whereas the physiologic importance of P-endorphin release into the systemic circulation is not certain, this molecule clearly has been shown to be an important neurotransmitter within the central nervous system. Endorphin has been invaluable as a research tool, but has not been clinically useful due to the avadabihty of plant-derived opiates. 

Morphine has certain undesirable side effects. Among these are respiratory depression, nausea, and vomiting, depression of the cough reflex, cardiovascular depression and hypotension, smooth muscle contraction (constipation), and histamine release (93). Morphine s onset of action, duration, and low therapeutic indices have prompted a search for a more effective opiate iv anesthetic. Extreme simplification of the complex morphine molecule has resulted in anilido —piperidines, the fentanyl class of extremely potent opiate iv anesthetics (118,119). 

In the strict sense, opiates are drugs which are derived from opium and include the natural products morphine, codeine, thebaine and many semi-synthetic congeners derived from them. In the wider sense, opiates are morphine-like drugs with non-peptidic structures. The old term opiates is now more and more replaced by the term opioids which applies to any substance, whether endogenous or synthetic, pqrtidic or non-peptidic, that produces morphine-like effects through an action on opioid receptors. 

Naltrexone completely blocks the effects of IV opiates, as well as drugp with agonist-antagonist actions (butorphanol, nalbuphine, and pentazocine). The mechanism of action appears to be the same as that for naloxone... 

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. 

Opiates produce more discreet inhibitory effects since they bind to and activate inhibitory opioid receptors which, due to their restricted distribution, cause less widespread effects than those of the barbiturates and alcohol. Activation of the opioid receptors leads to a decrease in release of other neurotransmitters (glutamate, NA, DA, 5-HT, ACh, many peptides, etc.) and direct hyperpolarisation of cells by opening of K+ channels and decreasing Ca + channel activity via predominant actions on the mu opiate receptor (see Chapter 12). 

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