Current Debates on the Neurotransmitter Basis of Morphine Dependency: A Review

Mohammad Reza Zarrindast PhD

Department of Pharmacology, Tehran University of Medical Sciences, Tehran, Iran

Introduction

Drug addiction has afflicted mankind for centuries, yet the mechanisms by which particular drugs lead to addiction, and the genetic factors that make some individuals particularly vulnerable to addiction, have remained elucive.¹ Three terms related to drug abuse are used commonly; tolerance, dependence, and addiction. Tolerance represents a reduced effect upon repeated exposure to a drug at a constant dose, or the need for an increased dose to maintain the same effect. Dependence is defined as the need for continued exposure to a drug so as to avoid a withdrawal syndrome (physical or psychological signs) when the drug is withdrawn. Addiction is defined as the compulsive use of a drug despite its adverse consequences.

The discovery of endogenous opiate receptors raised the possibility that opiate addiction might be mediated by changes in these receptors. A decade of research has failed to identify changes in the number of opioid receptors and also changes in levels of endogenous opioid peptides.^1,2 Some investigators have demonstrated that changes in the activity of G-protein and the second messenger and protein phosphorylation pathway mediate important aspects of opioid, and possibly cocaine, addiction in a number of drug-responsive brain regions.

The locus ceruleus (LC) is the largest noradrenergic nucleus in the brain and has served as a useful model of opiate action for many years. Pharmacological and biochemical studies have indicated that modulation of LC neuronal firing rates contributes to the physical aspects of opiate addiction, namely physical dependence and withdrawal in several species.^3,4

It has been proposed that the cAMP system in the LC can play a role in morphine dependence. Chronic administration of opiate leads to upregulation of the cAMP system, which increases the intrinsic excitability of LC neurons, and thereby accounts, at least in part, for opiate tolerance, dependence, and withdrawal exhibited by these neurons.¹ In the opiate-tolerant/dependent state, the combined presence of the opiate and the upregulated cAMP system would return LC firing rates toward pretreatment levels, whereas removal of the opiates would leave the upregulated cAMP system unopposed to withdrawal activation of the neurons.

The effects of a few neurotransmitters including nicotine, adenosine, GABA and cholecystokinine on dependence induced by morphine in animal experimental models are discussed. During the recent years great progress has been made in understanding the role of the afore-mentioned neurotransmitter systems in opiate dependence. In the present review, mostly based on animal experimentation, we will discuss some novel aspects of the interaction between different neurotransmitter systems.

The methods used for the experiments have been described elsewhere.^5,6

Nicotine and morphine dependence

Nicotine, the psychoactive component of tobacco products, is widely consumed by humans.^7,8,9 The drug exhibits several pharmacological actions in the central and peripheral nervous system and releases a number of neurotransmitters.¹⁰ Nicotine produces a variety of acute subjective effects in smokers, including increases in subjective reports of euphoria ^11,12 as

well as increased arousal and decreased fatigue.¹³ The drug affects many neurochemical systems, and particularly increases dopaminergic and cholinergic activity.^14,15 The drug is also involved in activating the opioid system(s).^10,16

These findings may have some bearing on the observation that opiate addicts and cigarette smokers display parallel emotional profiles during abstinence from their habits.¹⁷ Thus nicotine may alleviate at least some morphine abstinence signs. There has been a report that nicotine suppresses naloxone-induced jumping in morphine dependent mice.¹⁸ Recently we showed that nicotine can attenuate naloxone-induced jumping in morphine-dependent mice.⁵

This finding is important and shows that some kind of cross dependence may exist between nicotine and opiates. Different studies have demonstrated that tolerance develops to the depressant effects¹⁹ and analgesic effects of opiates in rodents.^20,21 There is also evidence showing that tolerance develops to some of the behavioral effects of nicotine.²² Animal research and human studies indicate that with repeated exposure, tolerance may also develop to many nicotine side effects. The effect of nicotine on naloxone induced jumping in the presence and absence of some drugs is shown in table 1.¹⁴

Nicotinic receptor stimulation activates enkephalin release and biosynthesis in discrete brain nuclei and adrenal chromaffin cells.^23,24 Therefore, nicotine may supress withdrawal jumping by such a mechanism. Mecamylamine, the central nicotinic receptor antagonist²⁵ but not hexamethonium, the peripheral nicotinic receptor antagonist, antagonized the nicotine response. Since the muscarinic receptor antagonist atropine did not alter the effect of nicotine, both central and peripheral muscarinic receptor involvement may be excluded. It has been reported that morphine inhibits the release of substance P from the spinal cord which in turn accumulates during the development of morphine dependence, possibly due to chronic inhibition of substance P.²⁶ There is also a report showing that the opioid receptor antagonist naloxone is able to release substance P through a presynaptic nicotinic receptor mechanism²⁷; it may be that nicotine suppresses withdrawal jumping by such a mechanism.

The selective dopamine D-1 receptor antagonist SCH23390, which has more than 500 times greater affinity for the dopamine D-1 than for the dopamine D-2 receptor^28,29, decreased the effect of nicotine on withdrawal jumping behavior induced by naloxone. Therefore, nicotine may also elicit its effect upon withdrawal jumping through a dopamine D-1 receptor mechanism. Nicotine receptors are located in the striatum and the mesolimbic system at the levels of cell bodies and terminals.^30,31 Activation of nicotinic receptors has been shown to be effective in stimulating the release of dopamine from the striatum and limbic system.^10,32,33 One may speculate that nicotine indirectly causes the inhibition of jumping through dopamine D-1 receptor stimulation. It has also been reported that the dopamine D-2 receptor agonist bromocriptine may potentiate morphine withdrawal signs³⁴, and that the dopamine D-1 and D-2 receptors exert opposite influences on morphine antinociception.³⁵

Administration of the dopamine D-2 receptor antagonist, sulpiride^36,37 did not alter the effect of nicotine. This drug did not affect withdrawal jumping itself. These data indicate that the dopamine D-2 receptor is not involved in the attenuation of withdrawal jumping. SCH23390 is thought to be a selective dopamine D-1 receptor antagonist; it binds with high affinity to 5-HT-2 receptors in the brain³⁸ and antagonizes 5-HT-2 receptor activation both centrally and peripherally.^39,40 The administration of 5-HT-2 receptor antagonists attenuates naloxone-precipitated withdrawal and quasi-morphine withdrawal.^41,42,43 This may account for the reduction of withdrawal jumping by SCH23390.

The a- and ß-adrenoceptor antagonists phen-oxybenzamine and propranolol did not alter the effect of nicotine. Therefore, the involvement of adrenergic mechanism(s) in this action of nicotine is unlikely.

Adenosine receptors and morphine dependence

Adenosine is a neuromodulator in the central nervous system.⁴⁴ Adenosine functions through different receptor sites named A₁, A₂, A₃ and A₄ receptors.^45,46 The A₁ and A₂ subtypes mediate different physiological actions of adenosine, display distinct structure-activity relationships and are distributed differently in tissues, including the brain.⁴⁷ Adenosine receptor agonists inhibit neuronal firing⁴⁸, reduce neurotransmitter release^49,50 and influence neurotransmitter second messengers.⁴⁵ Analgesic, anticonvulsant and hypnotic effects of adenosine receptors have been proposed.⁵¹

Our previous study also showed that adenosine receptor activation may influence the antinociception induced by GABA receptor agonists⁵² and stress-induced antinociception.^53,54 Morphine has been shown to release adenosine.⁵⁵ Adenosine-dependent mechanisms may be involved in catalepsy⁵⁶, morphine antinociception^55,57 and morphine tolerance.⁵⁸ Opioids are known to induce behavioral reinforcing effects⁵⁹ and a major restricting factor in the clinical use of opioids is the fear of drug dependence.⁶⁰ A change in synaptic regulation of dopamine cells in the ventral tegmentum area one week after termination of chronic treatment with morphine has been suggested. A possible long-lasting dopamine-adenosine interaction has been also implicated in dopamine-mediated craving and relapse to drug-seeking behaviors.⁶¹ Adenosine receptor agonists have shown to decrease naloxone-induced jumping in rats⁶² and in mice.^63,64 However, other investigators found no effect for adenosine receptor agonists in this respect in rats⁶⁵ or in mice.⁶⁶

Effects of adenosine receptor agonists and antagonists on naloxone-induced jumping is shown in table 2.⁶⁷ CHA (cyclohexyladenosine), and R-PIA (R(-)N⁶-(2-phenylisopropyl) adenosine, which are adenosine receptor agonists⁶⁸, decreased naloxone-induced jumping. Similar results have been reported by others.^62-64 In agreement with others⁶³, we did not observe sedation with low doses (0.1 and 0.25 mg/kg) of the adenosine agents. Thus the data may suggest that an adenosine-dependent mechanism(s) is involved in morphine dependence. However, there are reports that adenosine agonists do not influence naloxone-induced jumping.^65,66

The adenosine A₁ receptors are widely distributed in the brain.^46,47 Since the adenosine receptor agonists, CHA and R-PIA have more affinity for adenosine A₁ receptors^46,69, and the receptor A₁ antagonist, DPCPX (8-cyclopentyl-1,3-dipropylxanthine),^46,68 decreased the inhibitory response to CHA, adenosine A₁ receptors may be involved in the response. However, the adenosine A₁ receptor antagonist by itself also increased naloxone-induced jumping, which is consistence with some reports⁶⁵ but not with others.⁶⁶

The higher doses of the adenosine A₂ receptor agonist, CPCA (5'-(N-cyclopropyl)-carboxamidoadenosine,⁶⁹ also reduced naloxone-induced jumping and the effect was not antagonized by the adenosine A₁ or A₂ receptor antagonists.⁶⁷ This effect of CPCA may not be mediated through the adenosine receptor mechanism, since the drug doses were high, no adenosine receptor antagonists reduced the response and since other authors^62,65,66 reported no effect for adenosine A₂ receptors in this respect.

Adenosine A₁ and A₂ receptors have been shown to be present in the gastrointestinal tract.⁷⁰ The adenosine A₁ receptor agonists, CHA and R-PIA, and also a higher dose of an adenosine A₂ receptor agonist, CPCA, reduced the naloxone-induced diarrhea. The response elicited by the adenosine A₁ and A₂ receptor agonists was reduced by the adenosine A₁ receptor antagonist, DPCPX⁶⁸, and the adenosine A₂ receptor antagonist, DMPX (3,7-dimethyl-1-propargylxanthine)⁷¹, respectively. Thus stimulation of both the adenosine A₁ and A₂ receptors may be involved in the inhibition of diarrhea by these agents. The adenosine A₂ receptors are divided into two subtypes, A_2A and A_2B sites, and the adenosine A_2B receptors have been shown to be located in the gastric tissues.^46,47 Thus one may speculate that a peripheral mechanism is involved in the response induced by CPCA. However, there is a report indicating that the spinal cord may be a site of opioid effects on gastrointestinal transit in the mouse.⁷² Presynaptic adenosine A₁ receptor blockade may release adenosine, which in turn may activate postsynaptic adenosine receptors involved in the inhibition of diarrhea induced by naloxone. This hypothesis gains support from the fact that combination of adenosine A₂ receptor antagonist, DMPX with the adenosine A₁ receptor antagonist, DPCPX, is able to decrease this later effect induced by DPCPX. It should be mentioned that the results obtained with the adenosine receptor antagonists by some investigators⁶⁶ indicating that DPCPX has no effect on diarrhea and that DMPX increases the diarrhea induced by naloxone, are not in agreement with our findings.

GABA receptor agents and morphine dependence

The role of several neurotransmitters including serotonin, dopamine, GABA, adenosine aspartate, and excitatory amino acid, in morphine tolerance and withdrawal has been investigated. They seem to be involved in morphine tolerance and dependence.⁷³ A number of studies have also demonstrated that dopamine contributes to the expression of reward or morphine reinforcement.⁷⁴ Interactions of GABA with dopaminergic pathways^35,75, and adenosine⁵² may also indicate a greater complexity of the role of these neurotransmitters. It has been suggested that GABA-ergic and opiopeptidergic systems are interconnected through µ-opioid receptors.⁷⁶ GABA administration has also been shown to facilitate the development of tolerance and physical dependence.⁷⁷ The present results indicate that both baclofen and muscimol, which are GABA receptor agonists^78,79, inhibit naloxone-induced jumping behavior in morphine-dependent mice in a dose- dependent manner. The data also may indicate that GABA receptor mechanism(s) are involved in morphine jumping behavior (table 3).

The central inhibitory neurotransmitter, GABA^80-82, is found in all areas of the human brain.⁸³ It is well established that the GABA system is a target for a variety of centrally pharmacological agents including sedatives, analgesics and anticonvulsants.^84,85 GABA receptors in the brain have been classified as GABA_A and GABA_B.^86-88 Whereas GABA_A receptors are directly associated with a chloride channel, the GABA_B receptors seem to be G-protein coupled and linked to Ca²⁺ or K⁺ channels.⁸⁹ However, a third class of GABA binding site, the GABA_C sites, resembles the GABA_A receptor but is insensitive to bicuculline.⁹⁰

Since muscimol is a GABA_A receptor agonist⁷⁹ and baclofen acts on GABA_B receptors^78,79, it can be speculated that decreases in naloxone-induced jumping are mediated through both the GABA_A and GABA_B receptors. The inhibitory response induced by either i.p. or i.c.v.administration of the agonists, therefore, makes it likely that the responses to drugs are mediated through central GABA receptor mechanism(s). Our data are consistent with data which shows that chronic administration of morphine may modify central GABA receptors⁹¹, and the blockade of postsynaptic GABA receptors by bicuculline inhibits the development of tolerance and dependence⁷⁷, indicating that the central GABA system is involved in the expression of jumping behavior.

The i.c.v. but not i.p. administration of the competitive GABA_A receptor antagonist, bicuculline, or the non-competitive GABA_A receptor antagonist, picrotoxin⁹², also decreased naloxone-induced jumping. Bicuculline has been shown to release GABA, which in turn may reduce jumping behavior. The present data showed that i.p. injection of the higher dose of the GABA_B receptor antagonist, CGP35348⁹³, increased naloxone-induced jumping. This may indicate that a GABA_B receptor mechanism has a dominant inhibitory influence on this behavior. However, the i.c.v. injection of the antagonist did not alter the naloxone-induced jumping. Therefore, a possibility may exist that the response induced by i.p. administration of a higher dose of the drug is mediated through a peripheral mechanism. To clarify the exact mechanism(s) involved will require further work.

Cholecystokinin (CCK) and morphine dependence

The cholecystokinin octapeptide (CCK-8) is found throughout the mammalian nervous system and is present in the brain and spinal cord predominantly in the sulfated octapeptide form (CCK-8).⁹⁴ High concentrations of CCK have been identified in the cortical gray matter, periaqueductal gray, ventromedial thalamus and dorsal horn of the spinal cord, all of which are areas known to be involved in nociception.^94-96

It has been shown that the effects of CCK are mediated through at least two distinct types of binding sites. These have been referred to as type A (CCK_A) and type B (CCK_B) receptors for the predominant forms in the periphery and in the central nervous system (CNS), respectively. However, recent studies indicate that although CCK_B receptors predominate in the CNS, a smaller population of the CCK_A sites also exists.^95-100, The majority of CCK_B receptors are distributed throughout the brain and spinal cord.^95,98-100 There are good data to suggest that endogenous CCK may play an important physiological role in pain transmission by modulating CNS opiate mechanisms.^101-6 Our previous study showed that CCK-peptides may prevent tolerance to morphine antinociception.¹⁰⁷ In this review the possible mechanism(s) of CCK receptor agonists on development of morphine dependence has been discussed.¹⁰⁸ The effect of CCK receptor agonists and antagonists has been shown in tables 4 and 5. Our study showed that CCK receptor agonists caerulein, CCK-8 and unsulfated CCK-8 (CCK-8U) reduced the incidence of naloxone-induced jumping in morphine-dependent mice.¹⁰⁹ The data may indicate that CCK mechanism(s) may interact with the physical dependence of morphine. Caerulein and CCK-8 have high affinity for CCK_A and CCK_B receptors, therefore, it may be possible that CCK_A and CCK_B receptor sites are involved in the inhibition of morphine-dependence elicited by these peptides. CCK-8U which have high affinity for CCK_B but not for CCK_A receptors¹¹⁰, and also decrease the morphine withdrawal jumping. The response induced by CCK-8U seems to be lower than that elicited by CCK-8 or caerulein. However, it is suggested that the interaction between opioidergic and CCKergic neurotransmission at different stages of morphine treatment and withdrawal are not caused by changes of CCK receptor binding properties.¹¹¹

Although neurotransmitters such as norepinephrine, dopamine, serotonin and acetylcholine have been implicated in the pharmacological actions of morphine and in the phenomena of opioid withdrawal^112,113, the neurochemical basis of the CCK mechanism(s) in abstinence is unclear. In our study, the influences of the neurotransmitters on naloxone-induced jumping has been evaluated (Table 5). Functional relationship between CCK and dopamine in the different regions of brain has been demonstrated. There appears to be a complex interaction between dopamine and cholecystokinin systems in the nucleus accumbens.¹¹⁴ CCK-8 is colocalized with dopamine in a subpopulation of A10 dopamine-containing neurons.¹¹⁵ Moreover, the CCK-peptides may be released with dopamine. It is also possible that CCK-8 influence the release of dopamine or of CCK-8 itself by a presynaptic action. The naloxone-precipitated withdrawal jumping response in morphine-dependent animals has been suggested to be associated with an elevation of dopamine level.¹¹⁶

Dopamine is known to bind to separate receptor subtypes, namely D₁ and D₂.¹¹⁷ Present data showed that the D₁ dopamine receptor antagonist SCH23390¹¹⁸ did not alter attenuation of naloxone-induced jumping by CCK agonists in the morphine-dependent animals, thus the involvement of D₁ receptor sites in CCK mechanism seems unlikely. However, SCH 23390 can decrease the naloxone-induced jumping by itself. Our results indicate that D₂ dopamine receptor antagonists sulpiride³⁷ and pimozide¹¹⁹ potentiate CCK agonists-induced suppression of the withdrawal jumping. The D₂ dopamine antagonists sulpiride and pimozide also reduced naloxone-induced jumping by themselves. The data may be in agreement with those obtained by others where D₂ dopamine agonists increases¹²⁰ withdrawal jumping and may agree with the hypothesis that dopamine is important in the rewarding effects of abused drugs, and opioid withdrawal.¹²¹ The results may be consistent with the reports that activation of D₂ dopamine receptors may inhibit CCK release in the brain.¹²² However other reports indicate that dopamine receptor activation causes an increase¹²³ or decrease¹²⁴ in the withdrawal jumping respectively.

The a-and ß-adrenergic receptor antagonists phenoxybenzamine and propranolol did not alter naloxone-induced jumping in the presence or absence of caerulein. The same results have been shown previously.¹²⁵ Thus the involvement of adrenergic system(s) in the CCK-induced attenuation of naloxone-induced jumping seems unlikely.

Our data also indicates that 5-HT receptor antagonist methysergide reduced the naloxone-induced jumping in morphine-dependent mice. The 5-HT antagonists have been shown to attenuate the withdrawal jumping in morphine-dependent mice by others.⁴² In the present study, the antagonist tends to increase caerulein's response, but not significantly. Therefore the involvement of 5-HT mechanism in the caerulein's effect should be evaluated further.

The antimuscarinic atropine used in the study increased naloxone-induced jumping, which is also in agreement with results in other laboratories¹²⁶ that atropine increases, whereas cholinergic activation, attenuates abstinence syndrome. Overall, it may be concluded that CCK receptor system(s) may interact with D₂ dopamine receptor mechanism in attenuation of naloxone-induced jumping. Since CCK receptor agonists induce hypolocomotion¹²⁷, even this effect may interact with the naloxone-induced jumping. For exact clarification of the CCK mechanism, further experiments are required.

The topics discussed in this article clearly show that the opioid system is not the sole system involved in morphine dependence and a vast number of neurotrasmitter systems interact in this phenomenon. Thus, clinical intervention and the search for novel therapeutics for treating addiction should not be restricted to a few agents. Alteration of other apparently unrelated systems might render promising results. The author believes that the nicotinic system might be a proper candidate for intensive investigation. The impact of nicotine related agents on the jumping behavior of mice during withdrawal from morphine dependence strongly confirms this belief.

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