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 ventilatory minute volume (MV) at the doses of 3 to 100 pmol i.c.v. The doses of 30 and 100 pmol i.c.v. induced catalepsy. The effect of TAPS on MV was in negative correlation with the dose and the maximal response was achieved by the lowest (3 pmol) dose (+63 +/- 23%, P < .05). Morphine, an agonist at both mu 1 and mu 2 sites, at a dose of 150 nmol i.c.v. (equianalgesic to 100 pmol of TAPS decreased the MV by 30%, due to a decrease in ventilatory tidal volume. The antinociceptive effect of TAPS was antagonized by naloxone and the mu 1 receptor antagonist, naloxonazine. Naloxonazine also attenuated the catalepsy produced by 100 pmol of TAPS i.c.v. and the respiratory stimulation produced by 3 pmol of TAPS i.c.v. Pretreatment with 30 pmol of TAPS antagonized the respiratory 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%, respectively). After combined pretreatment with naloxonazine and TAPS, 1 nmol of dermorphin had no significant effect on ventilation. In contrast, pretreatment with a low respiratory stimulant dose (10 pmol i.c.v.) of dermorphin did not modify the effect of 1 nmol of dermorphin. In conclusion, the antinociceptive, cataleptic and respiratory stimulant effects of TAPS appear to be a related to its agonist action at the mu 1 opioid receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Paakkari
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P
Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Paakkari
I
I
Vonhof
S
S
Feuerstein
G
G
Sirén
A L
AL
D000595:Amino Acid Sequence; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002375:Catalepsy / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D008297:Male; D008969:Molecular Sequence Data; D009270:Naloxone / Q000031:analogs & derivatives / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D018847:Opioid Peptides; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000187:drug effects* / Q000502:physiology; D012119:Respiration / Q000187:drug effects*
D000700:Analgesics; D009842:Oligopeptides; D018847:Opioid Peptides; D017450:Receptors, Opioid, mu; C030058:dermorphin; D009270:Naloxone; C034643:naloxonazine; C053418:tyrosyl-arginyl-phenylalanyl-sarcosine