NDARC Technical Report No. 2 (1989)
PREFACE
Research involving the pharmacological manipulation of responsiveness to pain has contributed significantly to our understanding of how endogenous opiate systems operate to modulate the perception of, and reaction to pain. The manipulation of endogenous pain control systems is of particular interest to researchers from a variety of areas: those interested in the control of pain, those interested in adaptive behaviour, and those interested in the mechanisms of opiate tolerance and dependence.
In recent years, investigation of the role of learning processes both in drug tolerance and pain control has combined with physiological and pharmacological research to provide some provocative and influential theories of how the body responds to external factors such as drug administration and exposures to stress. In particular, research on Pavlovian conditioning of responses to drugs has an important role to play in elucidating the adaptive capacity of physiological systems.
Morphine and naloxone are the opioid agents most prominent in the study of both pain modulation and opioid tolerance and dependence. Morphine is employed as the prototypical opioid agonist (a drug which acts on the opioid receptor to produce morphine-like effects) which, at sufficient dosages, induces significant analgesia. In contrast, naloxone is seen as a "pure" opioid antagonist (a drug which blocks the effects of opioids at the receptor level but produces no effect itself) which is capable of blocking the potent opioid effects of morphine, and can itself induce the contrary effect of hyperalgesia (increased sensitivity to pain).
The experiments presented here add to a relatively new body of knowledge which indicates that chronic treatment with the opioid antagonist, naloxone, can activate endogenous pain control systems and produce analgesia in rats. This is a rather paradoxical finding since naloxone is known for its ability to reverse the analgesic effects of opioids and to itself produce hyperalgesia.
There are two general types of endogenous pain control systems, that is, systems within the body which are activated to reduce pain produced by external and internal causes. The best studied of these systems is the endogenous opioid system. As the name indicates, the 'endogenous' opioids are substances which are produced within the bodies oflower animals (such as rats and mice) and in humans which produce effects similar to those produced by the external opiates, morphine and heroin. A number of different endogenous opioids have been identified as well as a number of different opioid receptor types. The opioids, both endogenous and exogenous forms, produce their effects by attaching to receptors in the body. The drugs naloxone and naltrexone prevent the opioids from attaching to the receptor and thereby prevent them from producing their effects. They can also remove other opioids from the receptor and thus reverse their effects. It is thought that naloxone produces hyperalgesia by removing endogenous opioids from their receptors.
In the following studies it is shown that naloxone can produce analgesia in rats and that this analgesic response can be learned such that environmental stimuli that have been associated with the drug's injection can themselves come to elicit analgesia in the absence of the drug. It is also of interest that naloxone does not appear to produce this analgesic effect unless the repeated drug administrations are followed by exposurc to a painful stimulus (in this case, exposure to a heated surface; the degree of heat applied is sufficient to be uncomfortable for the rat but not so intense as to produce physical damage). It is suggested that the analgesic effect produced by naloxone is due to its blockade of the endogenous opioids. By preventing the opioids from acting to relieve pain, a second, 2 non-opioid pain control system is activated. Other research has shown that the endogenous opioid and non-opioid pain control systems seem to interact in this way - when one is active the other is inhibited.
We further assessed our hypothesis that the analgesic effect we were seeing in naloxonetreated rats was non-opioid in nature by conducting two standard assays for opioid involvement in a behaviour: blockade by naloxone and cross-tolerance with morphine. As stated earlier, endogenous opioids are blocked by naloxone, thus if a response cannot be reversed or blocked by naloxone, there is a reasonable chance that the response is not produced by an opioid mechanism. Second, opioid-mediatedresponses, especially those controlled by a particular type of receptor known as the mu receptor tend to show cross-tolerance with morphine. Tolerance to morphine is the reduction in effect of a given dose of morphine seen after repeated administrations of the drug. Cross-tolerance, as the name suggests, describes the phenomenon whereby if an organism is tolerant to the effects of one drug, it will also show tolerance to similar effects of similar-acting drugs. It has been demonstrated by other researchers that crosstolerance exists between endogenous opioids and morphine. Since neither of these two criteria were met by the rats who acquired naloxoneinduced analgesia, we reasoned that the analgesic effect we were seeing was mediated by a non-opioid mechanism. Furthermore, the analgesia acquired over repeated naloxone dosings in no way diminished the analgesic effect of an initial dose of morphine, but rather summated with this effect to produce a "superanalgesia".
By this stage, you may be saying, "Well this is all very interesting, but what does it have to do with drug dependence?" One example of the possible implications of these findings is in explaining certain types of drug interactions. For example, prior experience with one drug may influence an animal's or a person's reactions to other drugs. Take the case of polydrug abuse. It may be that if a person is very experienced with the effects of a depressant drug such as alcohol and he or she takes an opposite-acting stimulant drug such as cocaine in the place where alcohol is expected, the impact of the dose of cocaine may be increased. Such a finding has been reported for rats expecting pentobarbital, a barbiturate, and given cocaine (Hinson, Poulos & Cappell, 1982).
Drug tolerance is thought to result from adaptation to drug-induced changes in physiological states and behaviour. One model that has been proposed to explain these adaptive changes is the acquisition of compensatory or drug-opposite responding through Pavlovian conditioning (Siegel, 1983). The elicitation of compensatory responses while a drug is in the body acts to counteract the drug's effect and will result in tolerance (i.e., a reduction in the observed drug effect). However, the occurrence of these responses in the absence of drug administration might be perceived as withdrawal, a defining feature of physical dependence. It has been postulated that the elicitation of withdrawal-like symptoms in the presence of environmental stimuli previously associated with drug-taking may result in "craving", which, in turn, mediates further drug-taking. Extinction of these conditionally elicited "withdrawal symptoms" has been proposed as an important consideration in the effective treatment of drug dependence (Wikler, 1980).
The results from the experiments in which naloxone was employed as the unconditional stimulus (UCS) indicate that it is possible to establish conditional responses which mimic the effects of opioids. It is possible that these responses may effectively counteract the responses elicited in withdrawal. It would seem more efficacious to acquire a response opposite to that which is thought to promote "craving" than to simply extinguish that response. If opioid-like responses other than analgesia can be induced by naloxone, then it may be possible to effectively prevent the occurrence of their opposite counterparts in withdrawal through conditioning.
Wikler ( 1980) has recommended the use of naltrexone (a long-acting opioid antagonist) in the treatment of opioid dependence to facilitate extinction. According to Wilder's view, in the presence of naltrexone, opioid administration will be devoid of its reinforcing effects. Through repeated failed attempts to get "high" on opioids while under naltrexone, extinction of cue-elicited craving should occur as well as extinction of drug-acquisitive and drug-taking behaviours.
The work of Greeley, Poulos and Cappell (submitted) suggests a further benefit of antagonist treatment- the possible acquisition of responses which may counteract withdrawal. Other evidence which supports this hypothesis comes from experiments in which naloxone and naltrexone have been used to facilitate withdrawal from methadone (Charney et al., 1982; Riordan & Kleber, 1980). The withdrawal syndrome which accompanies abstinence from long-term methadone use encompasses an extended period of discomfort. It is the duration of this syndrome rather than its intensity that often leads to resumption of opioid use. Clinical studies have shown that the withdrawal period induced by abstinence from methadone can be decreased by chronic administration of naloxone or naltrexone (Charney et al., 1982; Riordan & Kleber, 1980). Although the intensity of the symptoms may be increased, the period over which they occur is significantly reduced. Concomitant administration of the -adrenergic agonist clonidine alleviates some of the withdrawal symptoms without provoking dependence itself.
The faster recovery under antagonist-precipitated withdrawal suggests that naloxone or naltrexone may enhance recovery of the endogenous systems which have been inhibited by repeated opioid administration. In addition to facilitating extinction of conditionally acquired responses, opioid antagonists may elicit their own adaptive responses which counter the withdrawal syndrome and enhance recovery to a drug-free, withdrawal-free state. These conclusions are speculative and require further research.