Opioid Overview

A wide-range of opioid agonists (drugs that activate a receptor by binding to it), including opium, heroin, morphine, percodan, and codeine, have addictive properties and are commonly abused. Opioid receptors are distributed throughout the brain and spinal cord and are known to mediate a number of activities including analgesia, species-typical behavior, and reward. Both endogenous opioids, which are naturally produced within the body, and exogenous opiates, which are produced outside the body, produce a variety of symptoms including pain relief, euphoria, respiratory depression (rarely clinically harmful), constipation, nausea, and vomiting. The effects are produced by opioids binding to opioid receptors throughout the body. Pharmacologists and molecular biologists have demonstrated that opioids act at three distinct classes of receptors: kappa, delta, and mu, although it is likely that additional subtypes exist (review in Dhawan et al., 1996). Since each class of receptor has a unique effect on the cell, the multitude of classes allows opioids to have a wide range of effects in the body.

It is, however, important to note that all classes of opioid receptors share key similarities. First, the receptors have a common general structure. Cloning demonstrates that the receptors are usually G protein-linked receptors imbedded in the plasma membrane of neurons (Satoh and Minami, 1995). Once the receptors are bound, a portion of the G protein is activated, which allows it to diffuse within the plasma membrane. The G protein moves within the membrane until it reaches its target, which is either an enzyme or an ion channel. Most often, the targets alter protein phosphorylation and/or gene transcription, which alter the short-term and long-term activity of the neuron, respectively.

Although opioids usually activate G proteins, it was recently demonstrated that opioids occasionally act independently of G proteins. A key study found that DAMGO, a selective mu receptor agonist, modulates calcium-dependent potassium channels independently of G proteins in bovine adrenal medullary chromaffin cells (Twitchell and Rane, 1994). The finding further highlights the complexity of the opioid system.

A second similarity is that activation any type of opioid receptors inhibits adenylate cyclase (Childers, 1991), which is an enzyme responsible for catalyzing numerous chemical reactions in neurons. Activation of each type of receptor appears to shares a common property, which allows them to alter adenylate cyclase activity. The common property/ies may explain why different types of opioid receptors occasionally have the same effect on a neuron. Even though opioid receptors share the ability to inhibit adenylate cyclase, each receptor subtype has unique series of effects that can not be produced by any other type of opioid receptor.

A final similarity is that all types of opioid receptors are present both presynaptically and postsynaptically in neurons (review in Simon, 1991). When acting at presynaptic receptors, the peptides function as neuromodulators affecting the release of neurotransmitters. At postsynaptic receptors, the peptides act as neurotransmitters by directly altering membrane potentials. The overall effect of opioids on a particular tissue depends upon the concentration and location of particular opioid receptors in the area.

Clinical and recreational opioid use is limited by the development of tolerance and dependence. Tolerance can be defined as the decreased potency of a drug, such that progressively larger doses must be used to achieve the same effect. Dependence, which is closely associated with tolerance, involves a continued need for opioid administration in order to prevent withdrawal symptoms. These symptoms include nausea, gastrointestinal disturbances, chills, and a general flu-like state in humans (Jaffe, 1980) and ptosis (drooping eyelid), teeth chattering, jumping, irritability, wet dog shakes, and diarrhea in animals (Wei et al., 1973). Lesion studies indicate that no single brain structure is responsible for the withdrawal symptoms (Adler et al., 1978).

The opioid system is connected with most neurotransmitter networks in the body. The interaction between the opioids and the dopaminergic system appears to be involved in addiction, tolerance, and withdrawal symptoms. The relevant interaction appears to occur along the mesolimbic projection, particularly in the ventral tegmental area (VTA) and nucleus accumbens (NA).

Dopamine Involvement in Opioid Reinforcement at the VTA

Numerous studies suggest that the VTA, a known center of DA activity, is involved in opioid reward. Rats will self-administer (Welzl et al, 1989) morphine when it is directly applied to the VTA. Additionally, rats will modify their place preference to obtain more morphine applied to the VTA (Philips and LePiane, 1980), which suggests that opioids in the VTA have a rewarding effect.

It has been further demonstrated that opiates applied to the VTA prompt animals to engage in behaviors increases dopamine activity. Specifically, VTA morphine causes rats to self-administer cocaine (Stewart, 1984), which is known to potentate DA activity. The study suggests that dopamine further augments the rewarding properties of opioids in the VTA. In fact, morphine enhances the firing frequency of mesolimbic DA neurons projecting from the VTA (Matthews and German, 1984), which provides firm evidence that opioids have an excitatory affect on dopamine. Not only do opioids have an excitatory effect on dopamine; the effects of opioids seem to be contingent upon dopamine activation. Dopamine antagonists, molecules that bind to the receptor and prevent it from being activated, block the effect of opioids by halting morphine-induced activities (Iwamoto, 1981).

Dopamine involvement in Opioid Reinforcement at the NA

While dopaminergic neurons project from the VTA to structures throughout the brain, the neurons heading to the NA have been repeatedly implicated in the rewarding properties of opioids. Systemic administration (into the body at large) of opiates increase dopamine turnover in the NA (Westerink et al, 1976), which suggests that opioids increase dopamine activity. It has been further demonstrated that opiates increase activity of early genes, c-fos, c-jun, and zif altering gene transcription (Graybiel et al., 1990), which suggests that opioids cause long-lasting and enduring changes in the cells of the NA.

Although dopamine excitation likely increases the rewarding effect of opioids, it appears that reinforcement is not contingent upon dopamine activation. A key study found that heroine self-administration continues after disruption of DA innervation in NA, which suggests that rewarding effects of opiates are only partially contingent on DA release in the NA (Koob and Bloom, 1988). The finding is consistent with the discovery that animals will self-administer opioids in the NA (Olds, 1982), which suggests that opioid activity in the NA has a rewarding effect independent of neurons from the VTA.

It is important to note that the animals will modify their behavior more to obtain opioids in the VTA (Olds, 1982), which suggests that the VTA activation produces a more rewarding effect than NA activation.

Another line of research suggests that dopaminergic input is not necessary for opioid reward. 6-OHDA lesions in NA, which specifically destroy dopaminergic neurons, did not effect lever press linked to opioid reward (Robbins et al., 1989).

Yet, it does appears that dopamine has an excitatory effect on opioid-induced reward. Dopamine antagonists slow response speed in reinforced tasks, but do not eliminate the response all together (Evenden and Robbins, 1983). A recent study also found potentiation of opioid activity by dopamine agonists, while dopamine antagonists inhibit opioid activity (Cook et al., 1999). On a cellular level, dopamine administration in NA tissue elicits changes in electrical activity when cell slices are placed in a test tube mimicking the brain's environment (Pennartz et al., 1992). In reviewing the body of research, dopamine seems to enhance the actions of opioids on reward in the NA, but does not appear to be required for reinforcement.

It is interesting to note that opioid and dopamine agonists alike, both substances associated with addiction, depress overall excitation in the NA (Pennartz et al., 1992). Yet, muscarinic agonists decrease excitation in the NA without altering addiction (Pennartz and Lopes da Silva, 1994).

NA involvement in opioid withdrawal and tolerance

The NA appears to be extremely sensitive to opioid withdrawal. Injecting an antagonist into a dependant animal can experimentally induce withdrawal. Low doses of the opiate antagonist, methylnaloxonium, disrupt operant performance when injected into NA of morphine-dependant rats (Stinus et al., 1990). Even though other structures were sensitive to withdrawal, the NA was by far the most sensitive (Stinus et al., 1990). Similarly, the same opioid antagonist increased animal's efforts to self-administer heroin (Koob, 1992) when injected in to rat NA, as if to avoid withdrawal.

The NA appears to not only be involved in opioid withdrawal, it also appears to play a role in opioid tolerance. A study examining NA dopamine concentrations found that concentrations are higher in tolerant rats than in controls (Johnson and Glick, 1992). Researchers have yet to demonstrate how the change in dopamine concentrations, associated with a change in reinforcement, plays a role in opioid tolerance.

A final hypothesis

DiChiara and North (1992) propose that opioids hyperpolarize GABA-interneurons in the VTA, which reduces the inhibition on dopaminergic neurons projecting to the NA. Consequently, dopaminergic neurons are overstimulated, which causes an increase in reinforcement associated with addiction. While the hypothesis is sound, it has not been conclusively proven. Preliminary evidence does support the contentions of DiChiara and North. A recent study found that opioid administration reduces GABA mRNA, which is the template and controller of GABA production (Mavridis and Besson, 1999).

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