Skip to main content
SpringerLink
Log in

Conditioned place aversion is a highly sensitive index of acute opioid dependence and withdrawal

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Conditioned place aversion (CPA) is known to be a sensitive measure of the aversive motivational state produced by opioid withdrawal in rats made chronically dependent on opioids.

Objective

The purpose of the present study was to examine the sensitivity of the CPA model in detecting a possible aversive state associated with naloxone-precipitated withdrawal from acute treatment with morphine.

Methods

Doses of morphine and naloxone, as well as number of conditioning trials, were systematically varied to determine the minimum conditions that would result in a detectable CPA in male Wistar rats. Naloxone (0.003–16.7 mg/kg) was administered 4 h after an injection of vehicle or morphine (1.0, 3.3, or 5.6 mg/kg) and immediately prior to confinement to one compartment of the conditioning apparatus; rats received either one or two such naloxone-conditioning trials (separate by 48 h).

Results

Morphine (5.6 mg/kg) followed 4 h later by vehicle produced no significant preference or aversion. In morphine-naive rats, 10 mg/kg naloxone was required to produce a significant CPA with two cycles of conditioning. When increasing doses of morphine were administered (1.0, 3.3, 5.6 mg/kg), significant increases in naloxone potency to elicit a CPA were observed (16-, 211-, and 1018-fold potency shifts, respectively). Naloxone potency after two pretreatments with 5.6 mg/kg morphine was comparable to its potency to elicit a CPA after chronic exposure to morphine. Although naloxone was still effective in producing a CPA after a single conditioning cycle (and hence a single morphine exposure), its effects were dramatically reduced relative to those seen with two conditioning cycles.

Conclusions

CPA is a reliable and sensitive index of the aversive motivational state accompanying withdrawal from acute opioid dependence.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.

Similar content being viewed by others

References

  • Adams JU, Holtzman SG (1990) Pharmacologic characterization of the sensitization to the rate-decreasing effects of naltrexone induced by acute opioid pretreatment in rats. J Pharmacol Exp Ther 253:483–489

    CAS  PubMed  Google Scholar 

  • Azorlosa JL, Stitzer ML, Greenwald MK (1994) Opioid physical dependence development: effect of single versus repeated morphine pretreatments and of subjects' opioid exposure history. Psychopharmacology 114:71–80

    Google Scholar 

  • Bickel WK, Stitzer ML, Liebson IA, Bigelow GE (1988) Acute physical dependence in man: effects of naloxone after brief morphine exposure. J Pharmacol Exp Ther 244:126–132

    CAS  PubMed  Google Scholar 

  • Cheney DL, Goldstein A (1971) Tolerance to opioid narcotics: time course and reversibility of physical dependence in mice. Nature 232:477–478

    CAS  PubMed  Google Scholar 

  • Delfs JM, Zhu Y, Druhan JP, Aston-Jones G (2000) Noradrenaline in the ventral forebrain is critical for opiate withdrawal-induced aversion. Nature 403:430–434

    Article  CAS  PubMed  Google Scholar 

  • Easterling KW, Holtzman SG (1997) Intracranial self-stimulation in rats: sensitization to an opioid antagonist following acute or chronic treatment with mu opioid agonists. J Pharmacol Exp Ther 281:188–199

    Google Scholar 

  • Easterling KW, Plovnick RM, Holtzman SG (2000) Acute opioid but not benzodiazepine dependence in rats responding for intracranial self-stimulation. Psychopharmacology 148:263–271

    Google Scholar 

  • Gellert VF, Sparber SB (1977) A comparison of the effects of naloxone upon body weight loss and suppression of fixed-ratio operant behavior in morphine- dependent rats. J Pharmacol Exp Ther 201:44–54

    CAS  PubMed  Google Scholar 

  • Gracy KN, Dankiewicz LA, Koob GF (2001) Opiate withdrawal-induced fos immunoreactivity in the rat extended amygdala parallels the development of conditioned place aversion. Neuropsychopharmacology 24:152–160

    Article  CAS  PubMed  Google Scholar 

  • Heishman SJ, Stitzer ML, Bigelow GE, Liebson IA (1989a) Acute opioid physical dependence in humans: effect of varying the morphine-naloxone interval. I. J Pharmacol Exp Ther 250:485–491

    CAS  PubMed  Google Scholar 

  • Heishman SJ, Stitzer ML, Bigelow GE, Liebson IA (1989b) Acute opioid physical dependence in postaddict humans: naloxone dose effects after brief morphine exposure. J Pharmacol Exp Ther 248:127–134

    Google Scholar 

  • Heishman SJ, Stitzer ML, Bigelow GE, Liebson IA (1990) Acute opioid physical dependence in humans: effect of naloxone at 6 and 24 hours postmorphine. Pharmacol Biochem Behav 36:393–399

    Article  CAS  PubMed  Google Scholar 

  • Jacob JJ, Michaud GM (1974) Acute physical dependence in the waking dog after a single dose of morphine. Psychol Med 4:270–273

    CAS  PubMed  Google Scholar 

  • Jacob JJC, Barthelemy CD, Tremblay EC, Colombel ML (1974) Potential usefulness of single-dose acute physical dependence on and tolerance to morphine for the evaluation of narcotic antagonists. Adv Biochem Psychopharmacol 8:299–318

    Google Scholar 

  • Jones RT (1980) Dependence in non-addict humans after a single dose of morphine. In: Way EL (ed) Endogenous and exogenous opiate agonists and antagonists. Pergamon Press, New York, pp 557–560

  • Kirby KC, Stitzer ML (1993) Opioid physical dependence development in human: effect of time between agonist pretreatments. Psychopharmacology 112:511–517

    CAS  PubMed  Google Scholar 

  • Kirby KC, Stitzer ML, Heishman SJ (1990) Acute opioid physical dependence in humans: effect varying the morphine-naloxone interval II. J Pharmacol Exp Ther 255:730–737

    CAS  PubMed  Google Scholar 

  • Kosersky DS, Harris RA, Harris LS (1974) Naloxone-precipitated jumping activity in mice following the acute administration of morphine. Eur J Pharmacol 26:122–124

    Article  CAS  Google Scholar 

  • Liu J, McElfresh A, Reis S, Fuqua L, Schulteis G (2002) Neuroadaptive processes in limbic and basal forebrain reward circuitry contribute to acute opioid dependence. 2002 Abstract Viewer/Itinerary Planner, Society for Neuroscience, Washington D.C., CD-ROM, program no. 310.10

  • Martin WR, Eades CG (1964) A comparison between acute and chronic physical dependence in the chronic spinal dog. J Pharmacol Exp Ther 146:385–394

    CAS  Google Scholar 

  • Meyer DR, Sparber SB (1977) Evidence of possible opiate dependence during the behavioral depressant action of a single dose of morphine. Life Sci 21:1087–1094

    Article  CAS  PubMed  Google Scholar 

  • Mucha RF (1987) Is the motivational effect of opiate withdrawal reflected by common somatic indices of precipitated withdrawal? A place conditioning study in the rat. Brain Res 418:214–220

    CAS  PubMed  Google Scholar 

  • Mucha RF, Herz A (1985) Motivational properties of kappa and mu opioid receptor agonists. Psychopharmacology 86:274–280

    Google Scholar 

  • Mucha RF, Iversen SD (1984) Reinforcing properties of morphine and naloxone revealed by conditioned place preferences: a procedural examination. Psychopharmacology 82:241–247

    Google Scholar 

  • Mucha RF, Millan MJ, Herz A (1985) Aversive properties of naloxone in non-dependent (naive) rats may involve blockade of central beta-endorphin. Psychopharmacology 86:281–285

    CAS  PubMed  Google Scholar 

  • Mucha RF, Gritti MD, Kim C (1986) Aversive properties of opiate withdrawal studied in rats. In: Holaday JW, Law P, Herz A (eds) Progress in opioid research. NIDA Res Monogr, pp 567–570

  • Nikpur J, Morse AC, Britton KT, Schulteis G (2000) Acute opioid dependence is characterized by brain reward deficits. Soc Neurosci Abstr 26:1576

    Google Scholar 

  • Parker LA, Joshi A (1998) Naloxone-precipitated morphine withdrawal induced place aversions: effect of naloxone at 24 hours postmorphine. Pharmacol Biochem Behav 61:331–333

    Article  CAS  PubMed  Google Scholar 

  • Parker LA, Cyr JA, Santi AN, Burton PD (2002) The aversive properties of acute morphine dependence persist 48 h after a single exposure to morphine. Evaluation by taste and place conditioning. Pharmacol Biochem Behav 72:87–92

    Article  CAS  PubMed  Google Scholar 

  • Ramabadran K (1983) Naloxone-precipitated abstinence in mice, rats and gerbils acutely dependent on morphine. Life Sci 33:385–388

    Article  CAS  PubMed  Google Scholar 

  • Ritzmann RF (1981) Opiate dependence following acute injections of morphine and naloxone: the assessment of various withdrawal signs. Pharmacol Biochem Behav 14:575–577

    Article  CAS  PubMed  Google Scholar 

  • Santi AN, Parker LA (2001) The dopamine antagonist, alpha-flupenthixol, interferes with naloxone-induced place aversion learning, but not with acute opiate dependence in rats. Pharmacol Biochem Behav 70:193–197

    Article  CAS  PubMed  Google Scholar 

  • Schnur P, Espinoza M, Flores R, Ortiz S, Vallejos S, Wainwright M (1992) Blocking naloxone-precipitated withdrawal in rats and hamsters. Pharmacol Biochem Behav 43:1093–1098

    Article  CAS  PubMed  Google Scholar 

  • Schulteis G, Markou A, Gold LH, Stinus L, Koob GF (1994) Relative sensitivity to naloxone of multiple indices of opiate withdrawal: a quantitative dose-response analysis. J Pharmacol Exp Ther 271:1391–1398

    CAS  PubMed  Google Scholar 

  • Schulteis G, Heyser CJ, Koob GF (1997) Opiate withdrawal signs precipitated by naloxone following a single exposure to morphine: potentiation with a second morphine exposure. Psychopharmacology 129:56–65

    Google Scholar 

  • Schulteis G, Heyser CJ, Koob GF (1999) Differential expression of response-disruptive and somatic indices of opiate withdrawal during the initiation and development of opiate dependence. Behav Pharmacol 10:235–242

    CAS  PubMed  Google Scholar 

  • Smits SE (1975) Quantitation of physical dependence in mice by naloxone-precipitated jumping after a single dose of morphine. Res Commun Chem Pathol Pharmacol 10:651–661

    CAS  PubMed  Google Scholar 

  • Sofuoglu M, Sato J, Takemori AE (1990) Maintenance of morphine dependence by naloxone in acutely dependent mice. J Pharmacol Exp Ther 254:841–846

    CAS  PubMed  Google Scholar 

  • Stinus L, Le MM, Koob GF (1990) The nucleus accumbens and amygdala as possible substrates for the aversive stimulus effects of opiate withdrawal. Neuroscience 37:767–773

    Google Scholar 

  • Tallarida RJ, Murray RB (1986) Manual of pharmacologic calculations with computer programs. Springer, Berlin, Heidelberg, New York

  • Walker JR, Ahmed SH, Gracy KN, Koob GF (2000) Microinjections of an opiate receptor antagonist into the bed nucleus of the stria terminalis suppress heroin self-administration in dependent rats. Brain Res 854:85–92

    CAS  PubMed  Google Scholar 

  • White-Gbadebo D, Holtzman SG (1994) Acute sensitization to opioid antagonists. Pharmacol Biochem Behav 47:559–566

    CAS  PubMed  Google Scholar 

  • Wiley JN, Downs DA (1979) Naloxone-precipitated jumping in mice pretreated with acute injections of opioids. Life Sci 25:797–802

    Article  CAS  PubMed  Google Scholar 

  • Young AM (1986) Effects of acute morphine pretreatment on the rate-decreasing and antagonist activity of naloxone. Psychopharmacology 88:201–208

    Google Scholar 

Download references

Acknowledgements

This research was supported by NIH grant DA-10475 (to G.S). Salary support for M.R.A. was provided by T32-DA-07277.

Author information

Author notes

  1. Marc R. Azar

    Present address: Behavioral Pharma Inc., 665 San Rodolfo Drive, STE 124 PMB184, Solana Beach, CA 92075, USA

Authors and Affiliations

  1. Department of Anesthesiology, UC San Diego School of Medicine and VA San Diego Healthcare System, 3350 La Jolla Village Drive, MC 125, San Diego, CA 92161-5085, USA

    Marc R. Azar & Gery Schulteis

  2. Department of Biobehavioral Health, The Pennsylvania State University, 311 East Health and Human Development Building, University Park, PA 16802, USA

    Marc R. Azar & Byron C. Jones

Authors
  1. Marc R. Azar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Byron C. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gery Schulteis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gery Schulteis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Azar, M.R., Jones, B.C. & Schulteis, G. Conditioned place aversion is a highly sensitive index of acute opioid dependence and withdrawal. Psychopharmacology 170, 42–50 (2003). https://doi.org/10.1007/s00213-003-1514-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-003-1514-y

Keywords

Search

Navigation