Skip to main content
SpringerLink
Log in

μ- and δ-opioid receptor antagonists precipitate similar withdrawal phenomena in butorphanol and morphine dependence

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

The relative involvement of μ- and δ-opioid receptors in the mediation of butorphanol-, as compared to morphine-, dependence was examined with the use of highly selective antagonists at μ- and δ-opioid receptors. Extracellular fluid levels of glutamate (Glu) and aspartate (Asp) were measured within the pontine locus coeruleus following precipitation of withdrawal from dependence on either butorphanol or morphine in conscious Sprague-Dawley rats. Dependence was induced by intracerebroventricular (i.c.v.) infusion of butorphanol (26 nmol/μl/h), morphine (26 nmol/μl/h) or saline vehicle (1 μl/h) for 3 days by means of an osmotic minipump. Microdialysis probes (2 mm tip) were inserted into the locus coeruleus 24 h before precipitation of withdrawal by i.c.v. injection of either the μ-opioid receptor antagonist,d-Pen-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; 4.8 nmol/5 μl or 48 nmol/5 μl), or the δ-opioid receptor antagonist, naltrindole (17-cyclopropylmethyl-6,7-dehydro-4,5-epoxy-3,14-dihydroxy-6,7,2′3′-indolmorphinan hydrochloride; 48 nmol/5 μl or 100 nmol/5 μl). Baseline levels of Glu ranged from 9.59±1.27 to 12.84 ±3.01 μM in the various treatment groups. Level of Asp were similar. Precipitation of withdrawal by CTOP elicited significant increases of Glu and Asp in both morphine- and butorphanol-dependent rats. Maximal increases in Glu of 425% and 258% above baseline levels were elicited in the first 15 min microdialysis sample following i.c.v. injection of CTOP in morphine- and butorphanol-dependent rats, respectively. Behavioral signs of withdrawal were greater in morphine than butorphanol-dependent groups. The i.c.v. treatment with naltrindole elicited increases in Glu and Asp that were similar, although less marked, than those precipitated by CTOP treatment. Administration of naltrindole produced equivalent signs of withdrawal in both morphine- and butorphanol-dependent rats. Withdrawal from dependence on both morphine and butorphanol is characterized by elevations in coerulear levels of excitatory amino acids. Responses elicited following the use of selective μ- and δ-opioid receptor antagonists to precipitate withdrawal suggest that the role played by these receptors in mediation of the signs and symptoms of withdrawal do not differ greatly between butorphanol- and morphine-dependent rats.

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

Similar content being viewed by others

References

  1. Abdelhamid, E. E., Sultana, M., Portoghese, P. S., and Takemori, A. E. 1991. Selective blockage of delta opioid receptors prevents the development of morphine tolerance and dependence in mice. J. Pharmacol. Exp. Ther. 258:299–301.

    PubMed  CAS  Google Scholar 

  2. Heel, R. C., Brogden, R. N., Speight, T. M., and Avery, G. S. 1978. Butorphanol: A review of its pharmacological properties and therapeutic efficacy.Drugs 16:473–505.

    PubMed  CAS  Google Scholar 

  3. Horan, P., and Ho, I. K. 1989. Comparative pharmacological and biochemical studies between butorphanol and morphine. Pharmacol. Biochem. Behav. 34:847–854.

    Article  PubMed  CAS  Google Scholar 

  4. Horan, P., and Ho, I. K. 1991. The physical dependence liability of butorphanol: a comparative study with morphine. Eur. J. Pharmacol. 203:397–391.

    Article  Google Scholar 

  5. Jaw, S. P., Hoskins, B., and Ho, I. K. 1993. Involvement of δ-opioid receptors in physical dependence on butorphanol. Eur. J. Pharmacol. 240:67–72.

    Article  PubMed  CAS  Google Scholar 

  6. Jaw, S. P., Hopkins, B., and Ho, I. K. 1993. Opioid antagonists and butorphanol dependence. Pharmacol. Biochem. Behav. 44: 497–500.

    Article  PubMed  CAS  Google Scholar 

  7. Martin, W. R., Eades, C. G., Thompson, J. A., Huppler, R. E., and Gilbert, P. E. 1976. The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J. Pharmacol. Exp. Ther. 197:517–532.

    PubMed  CAS  Google Scholar 

  8. Miyamoto, Y., Portoghese, P. S., and Takemori, A. E. 1993. Involvement of delta2 opioid receptors in the development of morphine dependence in mice. J. Pharmacol. Exp. Ther. 264:1141–1145.

    PubMed  CAS  Google Scholar 

  9. Monkovic, I., Conway, T. T., Wong, H., Perron, Y. G., Pachter, I. J., and Beieau, B. (1973). Total synthesis and pharmacological activities on N-substituted 3,14-dihydroxymorphinans, J. Am. Chem. Soc. 95:7910–7911.

    Article  PubMed  CAS  Google Scholar 

  10. Oh, K. W., Makimura, M., Jaw, S. P., Hoskins, B., and Ho, I. K. 1992. Effects of β-funaltrexamine on butorphanol dependence. Pharmacol. Biochem. Behav. 42:29–34.

    Article  PubMed  CAS  Google Scholar 

  11. Picker, M. J., Negus, S. S., and Craft, R. M. 1990. Butorphanol’s efficacy at mu and kappa opoid receptors: inferences based on the schedule-controlled behavior of nontolerant and morphine-tolerant rats and on the responding of rats under a drug discrimination procedure. Pharmacol. Biochem. Behav. 36:563–568.

    Article  PubMed  CAS  Google Scholar 

  12. Pircio, A. W., Gylys, J. A., Cananagh, R. L., Buynishi, J. P., and Bierwagen, M. E. 1976. The pharmacology of butorphanol, a 3,14-dihydroxymorphinan narcotic antagonist analgesic. Arch. Int. Pharmacodyn. 220:231–257.

    PubMed  CAS  Google Scholar 

  13. Gulya, K., Krivan, M., Nyolczas, N., Sarnyai, Z., and Kovacs, G. L. 1988. Central effects of the potent and highly selective μ opioid antagonistd-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) in mice. Eur. J. Pharmacol. 150:355–360.

    Article  PubMed  CAS  Google Scholar 

  14. Aghajanian, G. K. 1978. Tolerance of locus neurons to morphine and suppression of withdrawal response by clonidine. Nature 276: 186–188.

    Article  PubMed  CAS  Google Scholar 

  15. Feng, Y. Z., Zhang, T., Rockhold, R. W., and Ho, I. K. 1995. Increased locus coeruleus glutamate levels are associated with naloxone-precipitated withdrawal from butorphanol in the rat, Neurochem. Res. 20:745–751.

    Article  PubMed  CAS  Google Scholar 

  16. Redmond, D. E., Jr., and Krystal, J. H. 1984. Multiple mechanisms of withdrawal from opioid drugs. Annu. Rev. Neurosci. 7:443–478.

    Article  PubMed  CAS  Google Scholar 

  17. Foote, S. L., Bloom, F. E., and Aston-Jones, G. (1983). Nucleus locus coeruleus: new evidence of anatomical and physiological specificity. Physiol. Rev. 63:844–914.

    PubMed  CAS  Google Scholar 

  18. Rasmussen, K., and Aghajanian, G. K. (1989). Withdrawal-induced activation of locus coeruleus neurons in opiate-dependent rats: attenuation by lesions of the nucleus paragigantocellularis. Brain Res. 505:346–450.

    Article  PubMed  CAS  Google Scholar 

  19. Maldonado R., Stinus, L., Gold, L. H., and Koob, G. F. (1992). Role of different brain structures in the expression of the physical morphine withdrawal syndrome. J. Pharmacol. Exp. Ther. 261: 669–677,

    PubMed  CAS  Google Scholar 

  20. Aghajanian, G. K., Kogan, J. H., and Moghaddam, B. 1994. Opiate withdrawal increase glutamate and aspartate effux in the locus coeruleus: an in vivo microdialysis study. Brain Res. 636:126–130.

    Article  PubMed  CAS  Google Scholar 

  21. Hong, M., Milne, B., and Jhamandas, K. 1993. Evidence for the involvement of excitatory amino acid pathways in the development of precipitated withdrawal from acute and chronic morphine: an in vivo voltammetric study in the rat locus coeruleus. Brain Res. 623:131–141.

    Article  PubMed  CAS  Google Scholar 

  22. Zhang, T., Feng, Y. Z., Rockhold, R. W., and Ho, I. K. 1994. Naloxone-precipitated morphine withdrawal increases pontine glutamate levels in the rat. Life Sci. 55:PL25–31.

    Article  PubMed  CAS  Google Scholar 

  23. Rasmussen, K., Beitner-Jonson, D. B., Krystal, J. H., Aghajanian, G. K., and Nestler, E. J. 1990. Opiate withdrawal and the rat locus coeruleus: behavioral, electrophysiological, and biochemical correlates. J. Neurosci. 10:2308–2317.

    PubMed  CAS  Google Scholar 

  24. Rasmussen, K., Krystal, J. H., and Aghajanian, G. K. 1991. Excitatory amino acids and morphine withdrawal: differential effects of central and peripheral kynurenic acid administration. Psychopharmacology. 105:508–512.

    Article  PubMed  CAS  Google Scholar 

  25. Tanganelli, S., Antonelli, T., Morari M. Bianchi, C., and Beani, L. 1991. Glutamate antagonists prevent morphine withdrawal in mice and guinea pigs. Neurosci. Lett. 122:270–272.

    Article  PubMed  CAS  Google Scholar 

  26. Trujillo, K. A., and Akil, H. 1991. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801, Science 251:85–87.

    Article  PubMed  CAS  Google Scholar 

  27. Robers, H., Hyes, A. G., Birch, P. J., Traynor, J. R., and Lawrence, A. J. 1990. The selectivity of the opioid antagonist, naltrindole, for δ-opioid receptors. J. Pharm. Pharmacol. 42:358–359.

    Google Scholar 

  28. Paxinos, G., and Watson, C. 1986. The Rat Brain in Stereotaxic Coordinates, 2nd edition, Academic Press, Orlando, Florida.

    Google Scholar 

  29. Feng, Y. Z., Narita, M., Tseng, Y. T., Hoskins, B., and Ho, I. K. 1994. Crosstolerance between butorphanol and morphine in rats. Pharmacol. Biochem. Behavior. 49:657–661.

    Article  CAS  Google Scholar 

  30. Ellison, D. W., Beal, M. F., and Martin, J. B. 1987. Amino acid neurotransmitters in postmortem human brain analyzed by high performance liquid chromatography with electrochemical detection. J. Neurosci. Methods. 19:305–315.

    Article  PubMed  CAS  Google Scholar 

  31. McCarthy, P. S., Metacalf, G., and Howe, S. J. 1982. Continous infusion in rats as a method of assessing morphine-like physical dependence for opiates. Pharmacol. Biochem. Behav. 16:725–729.

    Article  PubMed  CAS  Google Scholar 

  32. McCarthy, P. S., and Howlett, G. J. 1984. Physical dependence induced by opiate partial agonists in the rat. Neuropeptides 5:11–14.

    Article  PubMed  CAS  Google Scholar 

  33. Brown, G. R. 1985. Stadol dependence: Another case. J. Am. Med. Assoc. 254:910.

    Article  CAS  Google Scholar 

  34. Evans, W. S., Bowen, J. N., Giordano, F.L., and Clark, B. 1985. A case of stadol dependence. J. Am. Med. Assoc. 253:2191–2192.

    Article  CAS  Google Scholar 

  35. Hoover, R. C., and Williams, R. B. 1985. Survey of butorphanol and nalbuphine diversion in U.S. hospitals. Am. J. Hosp. Pharm. 42:1111–1113.

    PubMed  CAS  Google Scholar 

  36. Jasinski, D. R., Preston, K. L. and Testa, M. 1988. Abuse potential evaluation of transnasally given butorphanol in humans. The Pharmacologist 30:A196.

    Google Scholar 

  37. Smith, S. G., and Davis, W. M. 1984. Nonmedical use of butorphanol and diphenhydramine. J. Am. Med. Assoc. 252:1010.

    Article  CAS  Google Scholar 

  38. Rasmussen, K. 1991. Afferent effects on locus coeruleus in opiate withdrawal, In Progress in Brain Research (Barnes, C. D., and Pompeiano, O., eds.), 88:207–216. Elsevier Science Publishers B. V., Amsterdam, Netherlands.

    Google Scholar 

  39. Feng, Y., Zhang, T., Rockhold, R. W. and Ho, I. K. 1994. Opioid receptor subtypes modulate pontine excitatory amino acid (EAA) levels differently in butorphanol and morphine dependence. Soc. Neurosci. Abst. 20:1167.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, 39216-4505, Jackson, Mississippi

    Y. Z. Feng, T. Zhang, S. Tokuyama, H. Zhu, R. W. Rockhold &  I. K. Ho

Authors
  1. Y. Z. Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Tokuyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H. Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R. W. Rockhold
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. I. K. Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I. K. Ho.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Feng, Y.Z., Zhang, T., Tokuyama, S. et al. μ- and δ-opioid receptor antagonists precipitate similar withdrawal phenomena in butorphanol and morphine dependence. Neurochem Res 21, 63–71 (1996). https://doi.org/10.1007/BF02527673

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02527673

Key Words

Search

Navigation