Drug Abuse

Chapter 2 Opioids

2.1. Opioids and opioid receptors

The opioids includes four different groups of compounds:

"True opiates" natural alkaloids derived from the opium poppy (papaver somniferum), such as morphine and codeine.

• Semi-synthetic opioids, structurally related to morphine (heroine).

• Synthetic opioids, structurally unrelated to morphine (fentanyl, methadone, pentazocine, etc).

• Endogenous opioid peptides (beta-endorphin, Met- and Leu-enkephalin, dynorphin A and B) were identified (Li et al., 1976; Hughes et al., 1975; Goldstein et al., 1979; Cone and Goldstein, 1982, respectively), following the discovery of stereospecific opioid binding site in the CNS (Pert and Snyder, 1973; Simon et al., 1973; Terenius, 1973).

 

Opioid receptors are distributed throughout the mammalian CNS (Atweh and Kuhar 1977a,b,c), but could also be found in periphery (Cox, 1988). Three main receptor types were identified N, x, and S (Martin et al., 1976; Lord et al., 1977; Chang et al., 1979). Recent studies have demonstrated the existence of two 8-opioid receptor subtypes (8, and 82) (Jiang et al., 1991). Table 1. shows the proposed classification of opioid receptors with corresponding agonists and antagonists.

2.2. Opioid dependence

Neuronal pathways and neurotransmitters. It is claimed that psychic dependence to opioids and many other drugs is regulated by three main anatomically well-defined brain areas (Koob, 1992). These areas are the followings: 1. ventral tegmental area (VTA), in which the cell bodies of the mesocorticolimbic dopamine (DA) system originate, 2. nucleus accumbens (NAc), which receives projections from the VTA, 3. ventral pallidum, which receives a major projection from the NAc.

Experimental studies showed that rats will self-administer opioids into the VTA, while opioid peptides injected into this brain region produce place preference (Di Chiara and North, 1992).

It has been shown that microinjection of the neurotoxin kainic acid, which destroys the cell bodies, but not fibres of passage, into the NAc markedly decreased an intravenous self-administration of both opioids and psychostimulants (Zito et al., 1985).

A similar effect was observed in the ventral pallidum following selective destruction of cell bodies by ibotenic acid (Hubner and Koob, 1987).

 

It was claimed that the DA neurons of the VTA are critical for opioid reinforcement (Bozarth and Wise, 1984). It seems that opioids excite DA neurons in the VTA, via preceptors located on GABA (y-amino butyric acid)-releasing neurons.

Opioids can induce a hyperpolarization of these GABA- neurons, by increasing the K' efflux. As a result, GABA release onto the DA cells is reduced and the firing rate of DA neurons is increased (Johnson and North, 1992; Fig.1). It is proposed that p- and -receptors are implicated in mediating the reinforcing actions of opioids, while x-receptors mediate their aversive actions (Di Chiara and Imperato, 1988; Spanagel et al., 1990).

 

Fig. 1. Schematic illustration of the way in which DA-containing neurons in the ventral tegmental area (VTA) are excited by opioids. GABA-containing interneurons are hyperpolarized by opioids acting at p-receptors. This results in decreased (-) GABA release and increased (+) firing and DA release of DA-containing neurons in the VTA towards the nucleus accumbens (NAc).

The level of other neurotransmitters, besides DA, is also deranged during opioid dependence. Several studies have been demonstrated that the excitatory amino acid (EAA) receptor system is involved in the process of opioid dependence. Morphine is known to inhibit the enzymes producing aspartic acid and glutamic acids (Koyuncuoglu et al., 1979, 1986) from asparagine and glutamine, respectively (Bielarczyk et al., 1986), resulting in the decreased level of EAAs. Accordingly, the chronic presence of opioid receptor agonists decreases a normal activation of NMDA receptors (Aanonsen and Wilcox, 1987; Tanganelli et al., 1991). Therefore, morphine dependence is associated with NMDA receptor up-regulation and/or supersensitivity (Koyuncuoglu et al., 1992a,b).

2.3. Withdrawal syndrome

Cessation of opioid agonist or administration of opioid receptor antagonist in opioiddependent subjects induces a withdrawal syndrome. Although physical dependence occurs mainly following chronic exposure to an opioid drug, a withdrawal syndrome can be precipitated in man (Bickel et al., 1988) and various animals (Martin and Eades, 1961;Way et al., 1969; Meyer and Sparber, 1977; Krystal and Redmond, 1983), following an acute opioid treatment as well.

Opioid physical dependence can be easily studied, since opioid withdrawal syndrome, induced by diverse opioid antagonists (Table 1.), can be abruptly abolished by opioid agonists (Wei et al., 1973a,b).

Table l. Opioid receptor classification and corresponding drugs, which interfere with these receptors (adapted from The RBI handbook of receptor classification, by Kebabian and Neumeyer (eds.), 1994)

Behaviour. Heroin or morphine have in men a short half-life (2 to 3 h). The onset of withdrawal symptoms occurs within 8 to 16 h after the last dose, and the peak effect is around 2-3 days. Methadone has a longer half-life (15-20 h) and the onset of withdrawal symptoms is within 2-3 days after the last use. However, the peak effect is around 1-2 weeks, and some symptoms persist for months before resolution occurs (Zweben and Payte, 1990). It has been demonstrated a long time ago (Himmelsbach et al., 1938, cited by Martin and Sloan, 1977) that the opioid withdrawal symptoms - nausea, vomiting, sweating, gooseflesh, diarrhoea, tremor, chills and fever - occurred predictably by discontinuing morphine administration in a person who had been maintained on a regular schedule for morphine injections with escalating dosage. Himmelsbach et al., (1938, cited by Martin and Sloan, 1977) developed a method of scoring the intensity of the withdrawal syndrome, placing emphasis on easily recognized objective disturbances rather than on subjective complaints.

The withdrawal syndrome in morphine-dependent rats includes whole-body shakes ("wet-dog" shakes), diarrhoea, escape jumps, teeth-chattering, salivation and irritability - aggression (Martin et al., 1963; Blasig et al., 1973; Wei et al., 1973a). Later on, several other withdrawal signs have been specified, for example sniffing, grooming, rearing, gnawing, penile-licking, mastication, ptosis, writhing and rhinorrhoea (Acquas and Di Chiara, 1992; Maldonado and Koob, 1993; Gold et al., 1994).

In order to classify the severity of withdrawal syndrome, several scoring systems were proposed. Some researchers divided the withdrawal symptoms in counted and checked signs (Maldonado and Koob, 1993), or in dominant and recessive ones (Blasig et al., 1973), while others provided signs with a weighting factor (Neal and Sparber, 1986). In our studies, described in chapters 5-7, the scoring system of Neal and Sparber (1986) has been used.

In table 2., are listed several withdrawal signs in morphine-dependent animals (rats and mice) in respect to their origin and involvement of specific neurotransmitters and/or receptor sites.

Neuronal pathways and neurotransmitters. The locus coeruleus (LC) is the main brain region playing an important role in the opioid withdrawal syndrome, but less in the opioid reinforcement. In contrast, the mesolimbic dopaminergic (DA-ergic) system mediates reinforcing properties of drugs, but is not extensively involved in drug withdrawal (Wise and Bozarth, 1987).

The LC is located on the floor of the fourth ventricle in the anterior pons. The small number of neurons provides widespread noradrenergic (NA-ergic) innervation to virtually all areas of the brain and spinal cord. Destruction of the LC decreased some opioid withdrawal signs, such as chewing and rearing in morphine-dependent rats (Maldonado and Koob, 1993). However, LC neurons recorded in slices from morphine-dependent rats do not exhibit a pronounced withdrawal hyperactivity (Christie et al., 1987), indicating that most of the withdrawal-induced activation of these cells observed in vivo is likely to be mediated by afferents to the LC. Studies revealed that the rostral medullary nucleus paragigantocellularis is the major excitatory input to LC neurons, acting primarily viaEAAs (Ennis and Aston-Jones, 1988; Hong et al., 1993).

The LC contains a high density of opioid receptors and it receives substantial direct enkephalin inputs. f3-Endorphin and dynorphin fibres are found in the LC area (AstonJones et al., 1993). Presynaptic opioid receptors located on terminals of central NA-ergic neurons, are probably responsible for the decreased release of NA (Arbilla and Langer, 1978) and the diminution of the LC terminal excitability that follows opioids exposure (Nakamura et al., 1982). In vitro studies revealed that opioids acting at N receptor may increase K+ efflux and inhibit Na' influx, which is followed by hyperpolarization of the LC neurons (Andrade et al., 1983).

Clonidine (beta2-agonist), a drug that decreases NA-ergic activity, blocks both opioid withdrawal symptoms and behaviour induced byelectrical stimulation of the LC (Maldonado and Koob, 1993). It has been shown that clonidine, similarly to opioids, elicit a hyperpolarization in LC neurons (Aghajanian, 1978). Coapplication of clonidine and opioid agonists shows a response similar to that evoked by either agonist alone (Aghajanian and Wang, 1987). This finding implicates that both the obeta2-adrenoceptor agonist andopioid agonists may affect K+ efflux in the same way.

Recently, it has been demonstrated that K'-channel openers can mimic the effects of morphine on neuronal K+ currents, and as a consequence can act as substituents for morphine during withdrawal process (Robles et al., 1994).

Second messenger systems

Acute opioid action (Fig. 2). Opioid-induced inhibition of LC neurons via increasing the conductance of a K+ channel and inhibition of a Na+-dependent inward current (Aghajanian and Wang, 1987) is mediated by the pertussis toxin-sensitive G-proteins (Blume, 1978). Administration of opioids leads to activation of the K+ channel by direct coupling of the opioid receptor to the K+ channel via a G-protein. In contrast, inhibition of the Na'-dependent current appears to be indirect. Namely, the Na+ current is normally activated by a cAMP (cyclic adenosine monophosphate)-dependent protein kinase, either through direct phosphorylation of the Na' channel or by phosphorylation of some associated proteins (Wang and Aghajanian, 1990). The opioid inhibition of the NA' current appears to be mediated via inhibition of adenylate cyclase (AC) and reduced levels of cAMP. Reduced levels of CAMP decrease cAMP-dependent protein kinase activity and phosphorylation of the responsible channel/pump or closely related associated proteins. In addition to reduced firing rates (due to hyperpolarization), inhibition of cAMP pathway decreases catecholamine synthesis via reduced phosphorylation of tyrosine hydroxylase. Biochemical studies have confirmed that opioids inhibit AC activity in the LC (Duman et al., 1988) and CAMP-dependent protein phosphorylation (Guitart and Nestler, 1989).

Table 2. Some withdrawal signs observed in rats and/or mice in respect to their origin (central) and the involved neurotransmitter/receptor sites.

1. Adams et al., Physiol & Behav 53: 1127, 1993; 2. Argiolas et al., Reg Pept 45: 139, 1993; 3. Ball et al., Physiol Behav 13: 123, 1974; 4. Baumeister et al., Neuropharmacol 28: 1151, 1989; 5. Baumeister et al., Neuropharmacol 31: 835, 1992; 6. Bedard and Pycock, Neuropharmacol 16: 663, 1992; 7. Bozarth and Wise, Science 224: 516, 1984; 8. Calvino et al., Brain Res 177: 19, 1979; 9. Gunne et al., Psychopharmacol 134, 1972; 10. Jones et al., Brain Res 560: 163, 1991; 11. Krane et al., New Eng Med 321: 1648, 1989; 12. Lammers et al., Brain Res 449: 294, 1988; 13. Lammers et al., Brain Res 449: 311, 1988; 14. Levin et al., Pharmacol Biochem Behav 34: 43, 1989; 15. Maldonado et al., J Pharmacol Exp Ther 261: 669, 1992; 16. Maldonado et al., Neuropharmacol 31: 1231, 1992; 17. Maldonado and Koob, Brain Res 605: 128, 1993; 18. Neal and Sparber, J Pharmacol Exp Ther 236: 157, 1986; 19. Patrick et al., Eur J Pharmacol 231: 243, 1993; 20. Pei et al., Eur J Pharmacol 230: 63, 1993; 21. Pothos et al., Brain Res 566: 348, 1991; 22. Stinus et al., Neurosci 37: 767, 1990; 23. Tremblay and Charton, Neurosci Lett 23: 137, 1981; 24. Tseng et al., Neuropharmacol 14: 247, 1975; 25. Ukai et al., Brain Res 557: 77, 1991; 26. Van Wimersma Greidanus et al., Ear J Pharmacol 173: 227, 1989; 27.Wei et al., J Pharmacol Exp Ther 185: 108, 1973; 28. Yukhananov et al., INRC-abstract p41, 1994.

Chronic opioid action. Following chronic opioid administration, the LC neurons develop tolerance to the prior described acute inhibitory actions as neuronal firing rates recover toward control levels (Aghajanian, 1978; Christie et al., 1987). It was suggested that during chronic exposure to opioids, long term adaptations in intracellular messenger proteins could occur, which could be involved in the process of cellular tolerance, dependence and withdrawal. It has been shown that chronic administration of opioids increases the levels of G-proteins (Nestler et al., 1989) and stimulates the AC (Duman et al., 1988), cAMP-dependent protein kinase (Nestler and Tallman, 1988) in the neurons of the LC. Tyrosine hydroxylase is also activated (Guitart et al., 1990), which is the ratelimiting enzyme, involved in the biosynthesis of catecholamine neurotransmitters (Fig. 2).

Fig. 2. Opioid actions in the locus coeruleus (LC). Acute administration of opioids inhibited (-) both adenylate cyclase and CAMP-dependent protein phosphorylation. Chronic administration of opioids increased (+) the levels of G-proteins and stimulated (+) the activity of adenylate cyclase, cAMP-dependent protein kinase and tyrosine hydroxylase.

In the chronic opioid-dependent state, the combined presence of opioids and the upregulated cAMP pathway would return the LC firing rate to control levels. Removal of the opioids would leave the up-regulated cAMP pathway unopposed, leading to withdrawal excitation of neuronal activity. Excitation of the LC neurons during withdrawal is necessary for producing many of the behavioral signs of opioid abstinence (Rasmussen et al., 1990; Maldonado and Koob, 1993).

In conclusion, all these findings indicate that upregulation of the cAMP pathway is a likely mechanism of opioid dependence in the LC. It is probably not the only mechanism, but this up-regulated cAMP pathway represent one of the examples in which a behavioral component (physical opioid dependence) can be correlated with biochemical and electrophysiological adaptations occurring in the neurons of the LC.

Following the chronic exposure to opioids, alterations on for example the molecular level (gene expression) have demonstrated (Nestler et al., 1993). However, these changes are not discussed in this thesis.

Treatment of opioid withdrawal syndrome. The expression of the morphine withdrawal syndrome in men/animals could be inhibited by opioids and non-opioids. Some examples are the followings:

•   Opioids. High doses (30 fold higher) of opioids terminated the precipitated withdrawal stimulus in animals (Holtzman, 1985) and men (Zweben and Payte, 1990), while the administration of enkephalinase inhibitors attenuated the expression of morphine withdrawal behaviour in rats and mice (Dzoljic, 1986; Dzoljic et al., 1986).

• Non-opioids.

-   Clonidine is effective in the treatment of the opioid withdrawal in humans (Gold et al., 1978; Kleber et al., 1980). In morphine-dependent rats, clonidine eliminated "wet-dog" shakes, diarrhoea and teeth-chattering and prevented the release of DA in the NAc (Romandini et al., 1984; Pothos et al., 1991).

-   5-HT Reuptake blockers (d-fenfluramine) attenuated opioid withdrawal jumping in rats (Cervo et al., 1981), a sign which is not influenced by clonidine.

-   K'-Channel openers (cromakalim and diazoxide) can mimic the effects of morphine on neuronal K` currents, and could act as substituents for morphine in the withdrawal syndrome (Robles et al., 1994).

- Ca'-Channel blockers (verapamil, nimodipine, flunarizine) reduced several signs of naloxone-precipitated withdrawal such as diarrhoea, ptosis and jumping in morphinedependent rats (Bongianni et al., 1986; Baeyens et al., 1987).

-   EAA receptor antagonists (discussed in chapter 3).

-   Nitric oxide synthase (NOS) inhibitors (discussed in chapters 4-5).

-   lbogaine and norharman (discussed in chapter 7)

2.4. Tolerance

Biochemical changes following tolerance

Opioid receptor system. It has been suggested that chronic opioid treatment alters the opiate receptor density in CNS (Collier, 1965). However, this subject is controversial. Some authors have reported a decrease in the number of p binding sites in tolerant animals (Rogers and El-Fakahany, 1986; Bhargava and Gulati, 1990; Abdelhamid and Takemori, 1991), while others showed no changes (Klee and Streaty, 1974; Nishino et al., 1990) or even an increase of p-receptor binding sites (Pert and Snyder, 1976; Brady et al., 1989).

Second messenger systems. There seemed to be some common mechanism underlying dependence (discussed on page 41) and tolerance. The up-regulated CAMP system likely contributes to tolerance by making it more difficult for opioids to inhibit cAMP system and corresponding increase of the Na'-dependent inward current. It is also possible that the upregulated cAMP system could result in greater levels of opioid receptor density through phosphorylation of the receptor. This hypothesis is based on observations that brief exposure to met-enkephalin desensitizes the p-opioid receptor in the LC and the evidence that agents which activate the cAMP pathway promote this desensitization (Harris and Williams, 1991). By promoting desensitization, the upregulated cAMP system in the tolerant state could lead to a reduced ability of opioids to activate acutely Gproteins and the K' channel. In rats chronically treated with morphine, p-receptors couple less well to G-proteins (Christie et al., 1987; Tao et al., 1993). This uncoupling of receptors and G-proteins may also contribute to the occurrence of opioid tolerance.

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