Reprinted from Science 244: 516-517 (1984).
Anatomically Distinct Opiate Receptor
Reward and Physical Dependence
Michael A. Bozarth & Roy A. Wise
Center for Studies in Behavioral Neurobiology
Department of Psychology
Montréal, Quebéc H3G 1M8 Canada
To identify the opiate receptor fields involved in opioid reward and physical dependence, we microinjected morphine directly into brain tissue. Experimentally naive rats learned to administer 100-ng infusions of morphine sulfate into the ventral tegmental area3 but failed to learn to press for the same infusions into other opiate receptor fields.4 To determine whether physical dependence is produced by this regimen, we challenged six subjects with the opiate receptor antagonist naloxone (5 mg/kg, injected intraperitoneally) and assessed the traditional dependence signs—escape from the test box, chattering teeth, and "wet-dog" shakes. None of these behaviors were induced by the naloxone challenge. Although this test suggested that the rewarding effect of morphine in these animals was not accompanied by physical dependence, it was possible that undetected dependence was sufficient to motivate drug-taking behavior.
Since the severity of withdrawal signs is exacerbated by increased drug exposure (Bläsig, Herz, Reinhold, & Zieglgänsberger, 1973; Kay, Gorodetzky, & Martin, 1967), we tested whether continuous, prolonged morphine infusions into the ventral tegmentum could produce physical dependence. Morphine was also infused into the periventricular gray substance and the ventricular space dorsal to this region. The drug (0.5 mg in 0.5 ml of vehicle per hour) was delivered for 72 hours through permanently implanted 21-gauge stainless steel cannulas connected by polyethylene tubing to osmotic minipumps (see Wei, 1981).5 The animals were then intraperitoneally injected with naloxone (5 mg/kg) and placed in a 25-cm Plexiglas cylinder. The number of escapes from the enclosure and the incidence of chattering teeth and of wet-dog shakes were noted for 20 minutes (see Figure 1). Long-term infusions into the periventricular gray produced clear signs of naloxone-precipitated withdrawal similar to that previously reported for both systemic and centrally administered morphine (Bläsig et al., 1973; Martin, Wikler, Eades, & Pescor, 1963;Wei, 1981; Wei & Loh, 1976).6 Some dependence signs were also seen after infusions into the ventral tegmentum, which lies 2 mm ventral to the injection site in the periventricular gray. Since intracranial drug injections can flow up the injection cannula to dorsal sites of action (Johnson & Epstein, 1975; Simpson & Routtenberg, 1973), the physical dependence produced by ventral tegmental morphine infusions may have resulted from the drug’s reaching the periventricular gray. To assess this possibility, additional animals were tested with cannulas angled to avoid penetration of the periventricular gray.7 When morphine was infused through angled cannulas, no signs of dependence were precipitated by the naloxone challenge (see Figure 1).
Figure 1: Naloxone-precipitated escape responding after long-term morphine infusions into various brain regions. Abbreviations: VTA-30, ventral tegmental area with angled cannulas (n=19); VTA, ventral tegmental area with unangled cannulas (n=12); PVG-R, rostral aspect of the periventricular gray substance (n=14); D3V, dorsal aspect of the third ventricle (n=13); and PVG-C, caudal aspect of the periventricular gray substance (n=20). Error bars depict standard errors of the means.
These data indicate that morphine injections into the ventral tegmental area that are sufficiently rewarding to establish the lever-pressing response in experimentally naive laboratory rats (Bozarth & Wise, 1981; see also endnote #3) do not produce the dependence signs usually associated with opioid addiction in this species. Physical dependence does result from the same regimen of morphine infusions into the periventricular gray region, but this site does not support intracranial morphine self-administration at doses that are effective in the ventral tegmentum (Bozarth & Wise, 1982).Thus, at least one rewarding consequence of opioids does not involve the dependence mechanism; this result confirms the view of several investigators that physical dependence is not a necessary condition for opioid reward (e.g., Deneau et al., 1969; McAuliffe & Gordon, 1980; Woods & Schuster, 1971). It remains possible that relief of withdrawal distress can add to the rewarding effect of morphine when systemic drug intake is prolonged,8 but the existence of a primary rewarding effect independent of any relief of withdrawal stress suggests the need to de-emphasize dependence in definitions of addiction and questions the utility of treatment programs aimed at simply alleviating withdrawal discomfort. The primary rewarding effect of morphine in the ventral tegmental area may explain two facts that are explained only with difficulty by homeostatic theories that stress the relief of withdrawal symptoms as the source of drug reward: opioids are potent rewards in naive subjects (Deneau et al., 1969; McAuliffe & Gordon, 1980; Woods & Schuster, 1971), and drug-oriented behavior is prevalent in addicts and experienced laboratory animals even after prolonged periods of abstinence.
Naloxone hydrochloride was a gift of the Endo Laboratories. We thank M. Asselin for her technical assistance. M.A.B. is a University Research Fellow sponsored by the Natural Sciences and Engineering Research Council of Canada (NSERC). Supported by grants from NSERC and the National Institute on Drug Abuse (United States).
1. The Prevalence of this notion is illustrated by the emphasis placed on attenuating withdrawal discomfort by research into the treatment of opioid addiction (e.g., Gold & Kleber, 1981; Gold, Redmond, & Kleber, 1978; Martin, 1977; Washton & Resnick, 1980). The presumed importance of physical dependence in opioid addiction is further exemplified by the emphasis on tests of physical dependence during the preclinical assessment of abuse potential of narcotic analgesics (e.g., Martin & Jasinski, 1977).
2. Although most methods of assessing drug reward require multiple injections, opiate reward can be demonstrated with a single injection (Bozarth & Wise, 1983).
3. Rats were tested in three 4-hour sessions. Each lever-press resulted in a 100-ng infusion of morphine sulfate (300 pmole) dissolved in 100 nl of Ringer’s solution. Animals in the yoked control condition rarely pressed the lever. The intracranial self-administration of morphine was blocked by naloxone; this blockade eliminates nonspecific drug action as an explanation of the rewarding effect (see Bozarth & Wise, 1981).
4. Intracranial self-administration was not established by injections into the nucleus accumbens, periventricular gray substance, or caudate nucleus (Bozarth & Wise, 1982); the conditioned place preference technique has also demonstrated that morphine microinjected into the ventral tegmentum is rewarding but microinjected into the periventricular gray substance is not (Phillips & LePiane, 1980).
5. Osmotic minipumps (Alzet Corp.) were implanted subcutaneously between the scapulae (see Wei, 1981). The dose and duration of the infusion (1.5 nmole/hour for 72 hours) were those reported to be optimal for producing physical dependence. With the upper incisor bar 5 mm above the interaural line, the stereotaxic coordinates were ventral tegmental area, 3.8 mm posterior to bregma, ±0.6 mm lateral to the midline, and 8.3 mm below the dura; for the rostral periventricular gray substance, the values were -3.8, ±0.6, and 5.8 mm; caudal periventricular gray substance, -6.8, ±0.6, and 4.5 mm; dorsal third ventricle, -3.8, ±0.0, and 4.9 mm (angled 15° from the midline).
6. Cannula placements had a statistically significant effect [F(4,78)=15.679, p < .001]; the rostral periventricular gray region produced the strongest escape responding [Tukey’s (a) test, p < 0.01 (Winer, 1971)]. Other signs of opiate withdrawal (e.g., teeth chattering, wet-dog shakes,) were also seen after chronic infusions into the periventricular gray substance, although these infusions failed to produce withdrawal diarrhea and weight loss.
7. Cannulas were angled 30° from the midline to avoid penetration of the periventricular gray region. Other subjects were tested after long-term infusions into the dorsal aspect of the third ventricle to determine if the dependence resulting from periventricular gray infusions were produced by ventricular diffusion. Several animals tested with angled cannulas for intracranial self-administration confirmed that this procedure did not alter the rewarding action of ventral tegmental morphine infusions.
8. Animals will work to avoid naloxone injection that precipitate withdrawal symptoms (Goldberg, Hoffmeister, Schichting, & Wuttke, 1971). Thus, the negatively reinforcing properties of withdrawal distress can maintain operant responding. Also, the potency of an opiate in supporting intravenous self-administration is related to its potency in producing physical dependence (Young, Swain, & Woods, 1981).
Bläsig, J., Herz, A., Reinhold, K., & Zieglgänsberger, S. (1973). Psychopharmacologia 33: 19.
Bozarth, M.A., & Wise, R.A. (1981). Life Sciences 28: 555.
Bozarth, M.A., & Wise, R.A. (1982). In L.S. Harris (Ed.), Problems of Drug Dependence, 1981 (National Institute on Drug Abuse Research Monograph 41: 158). Washington, DC: U.S. Government Printing Office.
Bozarth, M.A., & Wise, R.A. (1983). In L.S. Harris (Ed.), Problems of Drug Dependence, 1982 (National Institute on Drug Abuse Research Monograph 43: 171). Washington, DC: U.S. Government Printing Office.
Deneau, G., Yanagita, T., & Seevers, M.H. (1969). Psychopharmacologia 16: 30.
Dole, V.P. (1980). Scientific American 243: 138.
Eddy, N.B., Halback, H., Isbell, H., & Seevers, M.H. (1965). Bulletin of the World Health Organization 32: 721.
Gold, M.S., & Kleber, H.D. (1981). In H. Lal and S. Fielding (Eds.), The Psychopharmacology of Clonidine (pp. 299). New York: Liss.
Gold, M.S., Redmond, D.E., & Kleber, H.D. (1978). Lancet 1978-1: 929.
Goldberg, S.R., Hoffmeister, F., Schichting, U., & Wuttke, W. (1971). Journal of Pharmacology and Experimental Therapeutics 179: 268.
Jaffe, J.H. (1975). In L.S. Goodman and A. Gilman (Eds.), The Pharmacological Basis of Therapeutics (pp. 284). New York: Macmillan.
Johnson, A.K., & Epstein, A.N. (1975). Brain Research 86: 399.
Kay, D.C., Gorodetzky, C.W., & Martin, W.R. (1967). Journal of Pharmacology and Experimental Therapeutics 156: 101.
Lindesmith, A.R. (1980). In D.J. Lettieri, M. Sayers, and H.W. Pearson (Eds.), Theories on Drug Abuse: Selected Contemporary Perspectives (National Institute on Drug Abuse Research Monograph 30: pp. 34). Washington, DC: U.S. Government Printing Office.
Martin, W.R. (1977). In W.R. Martin (Ed.), Drug Addiction, vol. 2 (pp. 279). New York: Springer-Verlag.
Martin, W.R., & Jasinski, D.R. (1977). In W.R. Martin (Ed.), Drug Addiction, vol. 1 (pp. 159). New York: Springer-Verlag.
Martin, W.R., Wikler, A., Eades, C.G., & Pescor, F.T. (1963). Psychopharmacologia 4: 247.
McAuliffe, W.E., & Gordon, R.A. (1980). In D.J. Lettieri, M. Sayers, and H.W. Pearson (Eds.), Theories on Drug Abuse: Selected Contemporary Perspectives (National Institute on Drug Abuse Research Monograph 30: pp. 137). Washington, DC: U.S. Government Printing Office.
Nichols, J.R. (1965). Scientific American 212: 80.
Phillips, A.G., & LePiane, F.G. (1980). Pharmacology Biochemistry & Behavior 12: 965.
Schuster, C.R., & Thompson, T. (1969). Annual Reviews of Pharmacology 9: 483.
Simpson, J.B., & Routtenberg, A. (1973). Science 181: 1172.
Spragg, S.D.S. (1940). Comparative Psychological Monographs 15: 1.
Washton, A.M., & Resnick, R.B. (1980). American Journal of Psychiatry 137: 1121.
Weeks, J.R. (1962). Science 138: 143.
Wei, E. (1981). Journal of Pharmacology and Experimental Therapeutics 216: 12.
Wei, E., & Loh, H. (1976). Science 193: 1262.
Wikler, A., & Prescor, T. (1967). Psychopharmacologia 10: 255.
Winer, B.J. (1971). Statistical Principles in Experimental Design. New York: McGraw-Hill.
Woods, J.H., & Schuster, C.R. (1968). International Journal of Addictions 3: 231.
Woods, J.H., & Schuster, C.R. (1971). In T. Thompson and R. Pickens (Eds.), Stimulus Properties of Drugs (pp. 163). New York: Appleton-Century-Crofts.
Young, A.M., Swain, H.H., & Woods, J.H. (1981). Psychopharmacology 74: 329.
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