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 stress. 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 opiates. 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.

[1]  R. Wise,et al.  A psychomotor stimulant theory of addiction. , 1987, Psychological review.

[2]  M. Bozarth.  Physical dependence produced by central morphine infusions: An anatomical mapping study , 1994, Neuroscience & Biobehavioral Reviews.

[3]  Stanley J. Watson,et al.  Immunohistochemical localization of the cloned μ opioid receptor in the rat CNS , 1995, Journal of Chemical Neuroanatomy.

[4]  J. Kiss,et al.  Coexpression of dopamine D2, and substance P (neurokinin-1) receptor messenger RNAs by a subpopulation of cholinergic neurons in the rat striatum , 1993, Neuroscience.

[5]  G F Koob,et al.  Drug abuse: hedonic homeostatic dysregulation. , 1997, Science.

[6]  K. Befort,et al.  The delta-opioid receptor: isolation of a cDNA by expression cloning and pharmacological characterization. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Brigitte L. Kieffer,et al.  Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the µ-opioid-receptor gene , 1996, Nature.

[8]  A M Graybiel,et al.  The basal ganglia and adaptive motor control. , 1994, Science.

[9]  E. Borrelli,et al.  Absence of opiate rewarding effects in mice lacking dopamine D2 receptors , 1997, Nature.

[10]  Stephen P. Hunt,et al.  Altered nociception, analgesia and aggression in mice lacking the receptor for substance P , 1998, Nature.

[11]  B. Cox,et al.  Differential regulation of adenylyl cyclase activity by mu and delta opioids in rat caudate putamen and nucleus accumbens. , 1993, The Journal of pharmacology and experimental therapeutics.

[12]  R. Schwarting,et al.  Relationship between dopamine release in nucleus accumbens and place preference induced by substance P injected into the nucleus basalis magnocellularis region , 1995, Neuroscience.

[13]  T. Kaneko,et al.  Immunohistochemical localization of substance P receptor in the central nervous system of the adult rat , 1994, The Journal of comparative neurology.

[14]  C. Gerfen.  Substance P (neurokinin-1) receptor mRNA is selectively expressed in cholinergic neurons in the striatum and basal forebrain , 1991, Brain Research.

[15]  E. Nestler,et al.  Induction of chronic Fos-related antigens in rat brain by chronic morphine administration. , 1996, Molecular pharmacology.

[16]  S. Iversen,et al.  Behavioural effects of tachykinins and related peptides , 1986, Brain Research.

[17]  A. Saiardi,et al.  Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors , 1995, Nature.

[18]  R G Hill,et al.  Distinct mechanism for antidepressant activity by blockade of central substance P receptors. , 1998, Science.

[19]  A. Wheeldon,et al.  Pharmacological blockade or genetic deletion of substance P (NK1) receptors attenuates neonatal vocalisation in guinea-pigs and mice , 2000, Neuropharmacology.

[20]  G. Koob,et al.  Role of different brain structures in the expression of the physical morphine withdrawal syndrome. , 1992, The Journal of pharmacology and experimental therapeutics.

[21]  T. Unger,et al.  Effect of tachykinin receptor inhibition in the brain on cardiovascular and behavioral responses to stress. , 1997, The Journal of pharmacology and experimental therapeutics.

[22]  R. Wise,et al.  The neurobiology of addiction , 2019, Annals of the New York Academy of Sciences.

[23]  F. Bloom,et al.  Neuroscience of Addiction , 1998, Neuron.

[24]  D. van der Kooy,et al.  A single brain stem substrate mediates the motivational effects of both opiates and food in nondeprived rats but not in deprived rats. , 1992, Behavioral neuroscience.

[25]  D. Surmeier,et al.  Expression of the transcription factor ΔFosB in the brain controls sensitivity to cocaine , 1999, Nature.

[26]  T. Robbins,et al.  Drug addiction: bad habits add up , 1999, Nature.

[27]  D. Girdlestone,et al.  RP 67580, a selective antagonist of neurokinin-1 receptors, modifies some of the naloxone-precipitated morphine withdrawal signs in rats , 1993, Neuroscience Letters.