Increased morphine analgesia and reduced side effects in mice lacking the tac1 gene.
OBJECTIVE
Although morphine is a very effective analgesic, its narrow therapeutic index and severe side effects limit its therapeutic use. Previous studies indicated that the pharmacological responses of opioids are modulated by genetic and pharmacological invalidation of tachykinin receptors. Here we address the role of substance P and neurokinin A, which are both encoded by the tachykinin 1 (tac1) gene, as modulators of opioid effects.


METHODS
The analgesic and side effect potential of morphine was compared between wild-type and tac1 null mutant mice.


RESULTS
Morphine was a more potent analgesic in tac1 null mutant mice, that is, in the absence of substance P/neurokinin A signalling. Interestingly, the most serious side effect of acute morphine, that is respiratory depression, was reduced in tac1(-/-) animals. Comparing the addictive potential of morphine in wild-type and knockout animals we found that morphine preference was similar between the genotypes. However, the aversive effect of withdrawal precipitated by naloxone in morphine-dependent animals was significantly reduced in tac1 knockout mice. Behavioural sensitization, the underlying mechanism of addiction, was also significantly lower in tac1(-/-) mice.


CONCLUSIONS
The analgesic potential of morphine was increased in tac1 knockout mice. In contrast, both the ventilatory suppressing effect and the addictive potential of morphine were reduced. These results suggest that reducing activity of the tachykinin system may be a possible strategy to improve the pharmacological potential of morphine.
Bilkei-Gorzo
A
A
Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany. abilkei@unibonn.de
Berner
J
J
Zimmermann
J
J
Wickström
R
R
Racz
I
I
Zimmer
A
A
D000701:Analgesics, Opioid / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D016739:Behavior, Addictive / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000009:adverse effects / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D015288:Neurokinin A / Q000378:metabolism; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D012131:Respiratory Insufficiency / Q000139:chemically induced; D013373:Substance P / Q000378:metabolism; D015320:Tachykinins / Q000235:genetics*
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D015320:Tachykinins; D013373:Substance P; D009270:Naloxone; D009020:Morphine; D015288:Neurokinin A