Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Rewarding effects of opiates are absent in mice lacking the receptor for substance P

Nature volume 405, pages 180–183 (2000)Cite this article

Abstract

Modulation of substance P activity offers a radical new approach to the management of depression, anxiety and stress1,2,3. The substance P receptor is highly expressed in areas of the brain that are implicated in these behaviours, but also in other areas such as the nucleus accumbens which mediate the motivational properties of both natural rewards such as food and of drugs of abuse such as opiates4,5,6,7. Here we show a loss of the rewarding properties of morphine in mice with a genetic disruption of the substance P receptor. The loss was specific to morphine, as both groups of mice responded when cocaine or food were used as rewards. The physical response to opiate withdrawal was also reduced in substance P receptor knockout mice. We conclude that substance P has an important and specific role in mediating the motivational aspects of opiates and may represent a new pharmacological route for the control of drug abuse.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Locomotor behaviour does not increase in NK1-/- mice after morphine administration.
Figure 2: Lack of conditioned place preference induced by morphine in NK1-/- mice.
Figure 3: Conditioned place preference induced by food reward in NK1-/- mice and wild-type litter mates in food-deprived (FD) and food-sated (FS) animals.
Figure 4: Reduced conditioned response when place is paired with naloxone-induced withdrawal in NK1-/- mice.

Similar content being viewed by others

References

  1. De Felipe, C. et al. Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature 392, 394–397 (1998).

    Article  ADS  CAS  Google Scholar 

  2. Kramer, M. S. et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281, 1640–1645 (1998).

    Article  ADS  CAS  Google Scholar 

  3. Culman, J., Klee, S., Ohlendorf, C. & Unger, T. Effect of tachykinin receptor inhibition in the brain on cardiovascular and behavioural responses to stress. J. Pharmacol. Exp. Ther. 280, 238–246 (1997).

    CAS  PubMed  Google Scholar 

  4. Nakaya, Y. et al. Immunohistochemical localization of substance P receptor in the central nervous system of the adult rat. J. Comp. Neurol. 347, 249–274 (1994).

    Article  ADS  CAS  Google Scholar 

  5. Wise, R. A. Neurobiology of addiction. Curr. Opin. Neurobiol. 6 , 243–251 (1996).

    Article  CAS  Google Scholar 

  6. Robbins, T. W. & Everitt, B. J. Drug addiction: bad habits add up. Nature 398, 567–570 (1999).

    Article  ADS  CAS  Google Scholar 

  7. Koob, G. F., Sanna, P. P. & Bloom, F. E. Neuroscience of addiction. Neuron 21, 467–476 (1998).

    Article  CAS  Google Scholar 

  8. Koob, G. K. & Le Moal, M. Drug abuse: Hedonic homeostatic dysregulation. Science 278, 52– 70 (1997).

    Article  CAS  Google Scholar 

  9. Gerfen, C. R. Substance P (neurokinin-I) receptor mRNA is selectively expressed in cholinergic neurons in the striatum and basal forebrain. Brain Res. 556, 165–170 (1991).

    Article  CAS  Google Scholar 

  10. Maldonado, R. et al. Absence of opiate rewarding effects in mice lacking dopamine D2 receptors. Nature 388, 586– 589 (1995).

    Article  ADS  Google Scholar 

  11. Baik, J. H. et al. Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors. Nature 377, 424– 428 (1995).

    Article  ADS  CAS  Google Scholar 

  12. Wise, R. A. & Bozarth, M. A. A psychomotor stimulant theory of addiction. Psychol. Rev. 97, 469– 492 (1987).

    Article  Google Scholar 

  13. Bechara, A. & van der Kooy, D. A single brain stem substrate mediates the motivational effects of both opiates and food in nondeprived rats but not in deprived rats. Behav. Neurosci. 106 , 351–363 (1992).

    Article  CAS  Google Scholar 

  14. Maldonado, R., Girdlestone, D. & Roques, B. P. RP 67580, a selective antagonist of neurokinin-1 receptors, modifies some of the naloxone-precipitated morphine withdrawal signs in rats. Neurosci. Lett. 156, 135– 140 (1993).

    Article  CAS  Google Scholar 

  15. Matthes, H. W. D. et al. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the m-opioid-receptor gene. Nature 383, 819–823 (1996).

    Article  ADS  CAS  Google Scholar 

  16. Rupniak, N. M. J. et al. A Pharmacological blockade or genetic deletion of substance P (NK1) receptors attenuates neonatal vocalisation in guinea-pigs and mice. Neuropharmacology (in the press).

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

    CAS  Google Scholar 

  18. Bozarth, M. A. Physical dependence produced by central morphine infusions: an anatomical mapping study. Neurosci. Biobehav. Rev. 18, 373–383 (1994).

    Article  CAS  Google Scholar 

  19. Mansour, A., Fox, C. A., Burke, S., Akil, H. & Watson, S. J. Immunohistochemical localization of the cloned mu opioid receptor in the rat CNS. J. Chem. Neuroanat. 8, 283–305 (1995).

    Article  CAS  Google Scholar 

  20. Kieffer, B. L., Beford, K., Gaveriaux-Ruff, C. & Hirth, C. G. The delta-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization. Proc. Natl Acad. Sci. USA 89, 12048–12052 (1992).

    Article  ADS  CAS  Google Scholar 

  21. Izenwasser, S., Buzas, B. & Cox, B. M. Differential regulation of adenylyl cyclase activity by mu and delta opioids in rat caudate putamen and nucleus accumbens. J. Pharmacol. Exp. Ther. 267, 145– 152 (1993).

    CAS  PubMed  Google Scholar 

  22. Nye, H. E. & Nestler, E. J. Induction of chronic Fos-related antigens in rat brain by chronic morphine administration. Mol. Pharmacol. 49, 636–645 ( 1996).

    CAS  PubMed  Google Scholar 

  23. Kelz, M. B. et al. Expression of the transcription factor delta FosB in the brain controls sensitivity to cocaine. Nature 401, 272–276 (1999).

    Article  ADS  CAS  Google Scholar 

  24. Aubry, J. M., Schulz, M. F., Pagliusi, S., Schulz, P. & Kiss, J. Z. Coexpression of dopamine D2 and substance P (neurokinin-1) receptor messenger RNAs by a subpopulation of cholinergic neurons in the rat striatum. Neuroscience 53, 417–424 (1993).

    Article  CAS  Google Scholar 

  25. Graybiel, A. M., Aosaki, T., Flaherty, A. W. & Kimura, M. The basal ganglia and adaptive motor control. Science 265, 1826–1831 (1994).

    Article  ADS  CAS  Google Scholar 

  26. Elliott, P. J. & Iversen, S. D. Behavioural effects of tachykinins and related peptides. Brain Res. 381, 68–76 (1986).

    Article  CAS  Google Scholar 

  27. Boix, F., Sandor, P., Nogueira, P. J., Huston, J. P. & Schwarting, R. K. Relationship between dopamine release in nucleus accumbens and place preference induced by substance P injected into the nucleus basalis magnocellularis region. Neuroscience 64, 1054–1055 (1995).

    Article  Google Scholar 

  28. Shaham, Y. & Stewart, J. Stress reinstates heroin-seeking in drug-free animals: an effect mimicking heroin, not withdrawal. Psychopharmacol. 119, 334–341 (1995).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. O'Brien, J. A. Perez De Gracia, and P. Mantyh, R. Maldonado and C. Stanford for reading and commenting on the manuscript, and N. Rupriak for sharing unpublished data.

Author information

Authors and Affiliations

  1. Instituto de Neurosciencias, Universidad Miguel Hernandez, Ap. correos 18, Alicante, 03550, Spain

    Patricia Murtra & Carmen De Felipe

  2. Department of Anatomy and Developmental Biology, University College London, Medawar Building, Gower Street, London, WC1E 6BT, UK

    Anne M. Sheasby & Stephen P. Hunt

Authors
  1. Patricia Murtra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anne M. Sheasby
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen P. Hunt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carmen De Felipe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen P. Hunt.

Supplementary information

41586_2000_BF35012069_MOESM1_ESM.doc

Table 1: Incidence of behavioural signs of abstinence measured during naloxone-precipitated morphine withdrawal syndrome in wild and NK1 -/- mice. (DOC 24 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Murtra, P., Sheasby, A., Hunt, S. et al. Rewarding effects of opiates are absent in mice lacking the receptor for substance P. Nature 405, 180–183 (2000). https://doi.org/10.1038/35012069

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35012069

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing