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


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.

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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.

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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and P. Mantyh, R. Maldonado and C. Stanford for reading and commenting on the manuscript, and N. Rupriak for sharing unpublished data.

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Correspondence to Stephen P. Hunt.

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

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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).

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