Opioid neurotransmitters

The intoxicating effects of opioids appear to be due to their action as agonists on mu (p) receptors of the opioid neurotransmitter system. Competitive p opioid antagonists such as naloxone and naltrexone acutely reverse many of the adverse effects of opioids. To date we do not have specific antagonists for most other abused substances, so rapid pharmacologic reversal of intoxication is usually not possible. 

Spinorphin has antinociceptive potency, and its effect may be due to the inhibition of the degradation of endogenous opioids (Honda et al., 2001 Maldonado et al., 1994 Schmidt et al, 1991 Yamamoto et al., 2002b Yu et al., 2004). Spinorphin administered ICV did not influence acute pain sensitivity, but potentiated the effects of Leu-ENK. It inhibited the nociceptin-induced allodynia in a dose-dependent manner after IT administration, which was reversed by naloxone (Honda et al., 2001). Thus, spinorphin is not a real endogenous opioid neurotransmitter, but it might enhance the effect of Leu-ENK through inhibition of the degradation of ENK. 

These heterocyclic opioid agents, with a diverse structure, act by binding to one or more of the opioid receptor sites which are to be found on neural (and some other sites) in the central and peripheral nervous systems. It is now recognized that these are the natural receptor sites for recognition of the endogenous members of the peptide opioid neurotransmitters families, which are found in neuronal tissue of the brain and elsewhere. 

Zubieta JK, Heitzeg MM, Smith YR, et al. COMT vall58met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science 2003 299(5610) 1240-3. 

Opioid neurotransmitters in the brain are peptides that modulate pain perception and/or the reaction to perceived pain they include the enkephalins, endorphins, dynorphins, and neoendorphins. All exert their effects by binding to specific types of opiate receptors that are located in various parts of the CNS, but particularly in those regions... 

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. ... 

The effects of lead on the opioid neurotransmitters, the enkephalins, has recently been studied. An increase in striatal enkephalins has been observed following a three month period of continuous lead exposure (Govoni et al., 1980 Memo et al., 1980c). Studies using lower and shorter lead exposures have shown a depression of enkephalin levels in the striatum and a delay in the ontogeny of this neurotransmitter (Winder et al., 1984b). 

The principal hormones of the human posterior pituitary include the two nonapeptides, oxytocin [50-56-6] and arginine vasopressin [11000-17-2] (antidiuretic hormone, ADH). Many other hormones, including opioid peptides (see Opioids, endogenous), cholecystokinin [9011-97-6] (CCK) (see Hormones, BRAIN oligopeptides), and gastrointestinal peptides, also have been located in mammalian neurohypophysis (6), but are usually found in much lower concentrations (7). Studies have demonstrated that oxytocin and vasopressin are synthesized in other human organs, both centrally and peripherally, and there is considerable evidence for their role as neurotransmitters (see Neuroregulators) (8). 

Opioids G-protein coupled p-, 5-, k-receptors l cAMP l Ca2+ currents t K+ currents l Excitability of peripheral and central neurons l Release of excitatory neurotransmitters p, 5 sedation, nausea, euphoria/re-ward, respiratory depression, constipation k dysphoria/aversion, diuresis, sedation... 

The neuropeptides are peptides acting as neurotransmitters. Some form families such as the tachykinin family with substance P, neurokinin A and neurokinin B, which consist of 11 or 12 amino acids and possess the common carboxy-terminal sequence Phe-X-Gly-Leu-Met-CONH2. Substance P is a transmitter of primary afferent nociceptive neurones. The opioid peptide family is characterized by the C-terminal sequence Tyr-Gly-Gly-Phe-X. Its numerous members are transmitters in many brain neurones. Neuropeptide Y (NPY), with 36 amino acids, is a transmitter (with noradrenaline and ATP) of postganglionic sympathetic neurones. 

A 17 amino acid long peptide sequentially related to opioid peptides in particular dynorphin A. OFQ/N is inactive at the 5, k, and p opioid receptors, but binds to its own NOP receptor (formerly ORL-1, for opioid receptor like-1). In contrast to opioid peptides, OFQ/N has no direct analgesic properties. OFQ/N is the first example for the discovery of a novel neurotransmitter from tissue extracts by using an orphan receptor as bait. Centrally administered in rodents, OFQ/N exerts anxiolytic properties. OFQ/N agonists and antagonists... 

They act as analgesics by inhibiting release of nociceptive neurotransmitters from primary afferent terminals as well as by depressing post-synaptic potentials on second order neurons. Opioid receptors are also present on some nociceptors and their expression and peripheral transport is increased upon peripheral inflammation. Peripheral opioid analgesia has been established in animal models. Although clinical studies have yielded mixed results so far, this field holds great promise. Despite side effects, such as euphoria, dysphoria, sedation, respiratory depression and obstipation and tolerance and dependence phenomena which arise upon... 

Lthanol (or alcohol) is a two-carbon molecule that, in contrast to many other drugs of abuse, such as opioids, cocaine, and nicotine, does not bind to specific brain receptors. Nonetheless, alcohol affects a variety of neurotransmitter systems, including virtually all of the major systems that have been associated with psychiatric symptoms (Kranzier 1995). Alcohol affects these neurotransmitter systems indirectly by modifying the composition and functioning of... 

One problem with both these theories is that disruption of noradrenergic transmission by selective adrenoceptor antagonists has little impact on the development of escape deficits. However, such antagonists do prevent the reversal of learned helplessness by antidepressants (reviewed by Stanford 1995). Also, it would be most unlikely that a deficit in only one neurotransmitter system fully accounts for learned helplessness. Indeed, there is plenty of evidence for a role for 5-HT in learned helplessness for instance, this behaviour is reversed by microinjection of 5-HT into the prefrontal cortex (Davis et al. 1999). Finally, it is clear that opioid, GABAergic and cholinergic systems (among others) are all linked with this behavioural deficit and even dihydropyridine antagonists of Ca + channels prevent its development. 

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). 

In rodents, PCP produces not only ataxia, but also stereotyped behavior and hyperactivity. The PCP-induced stereotyped behavior is thought to be due to changes in serotonergic and dopaminergic systems (Nabeshima et al. 1983 Martin et al. 1979 Sturgeon et al. 1981). It is not known whether PCP receptors mediate PCP-induced hyperactivity or stereotyped behavior or even the effect on neurotransmitter systems. It is also possible that mu, kappa, or sigma opioid receptors are involved (Castellani et al. 1982). 

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