DERMORPHIN ANALOG TYR-D-ARG2-PHE-SARCOSINE-INDUCED OPIOID ANALGESIA AND RESPIRATORY STIMULATION - THE ROLE OF MU(1)-RECEPTORS

Tyr-D-Arg2 -Phe-sarcosine4 (TAPS), a mu-selective tetrapeptide analog of dermorphin, induced sustained antinociception and stimulated ventil atory minute volume (MV) at the doses of 3 to 100 pmol i.c.v. The dose s of 30 and 100 pmol i.c.v. induced catalepsy. The effect of TAPS on M V was in negative correlation with the dose and the maximal response w as achieved by the lowest (3 pmol) dose (+63 +/- 23%, P < .05). Morphi ne, an agonist at both mul and mu2 sites, at a dose of 150 nmol i.c.v. (equianalgetic to 1 00 pmol of TAPS decreased the MV by 30%, due to a decrease in ventilatory tidal volume. The antinociceptive effect of T APS was antagonized by naloxone and the mul receptor antagonist, nalox onazine. Naloxonazine also attenuated the catalepsy produced by 100 pm ol of TAPS i.c.v. and the respiratory stimulation produced by 3 pmol o f TAPS i.c.v. Pretreatment with 30 pmol of TAPS antagonized the respir atory depression induced by the mu opioid agonist dermorphin (changes in MV after dermorphin alone at 1 or 3 nmol were -22 +/- 10% and -60 /- 9% and, after pretreatment with TAPS, +44 +/- 11% and -18 +/- 5%, r espectively). After combined pretreatment with naloxonazine and TAPS, 1 nmol of dermorphin had no significant effect on ventilation. In cont rast, pretreatment with a low respiratory stimulant dose (10 pmol i.c. v.) of dermorphin did not modify the effect of 1 nmol of dermorphin. I n conclusion, the antinociceptive, cataleptic and respiratory stimulan t effects of TAPS appear to be a related to its agonist action at the mul opioid receptors. TAPS did not induce respiratory depression (a mu 2 opioid effect) but antagonized the respiratory depressant effect of another mu agonist. Thus, in vivo TAPS appears to act as a mu2 recepto r antagonist.