Morphine and morphine-6beta-glucuronide-induced feeding are differentially reduced by G-protein alpha-subunit antisense probes in rats.
Although morphine and its active metabolite, morphine-6beta-glucuronide (M6G), each induce mu-opioid receptor-sensitive feeding, different antisense oligodeoxynucleotide (AS ODN) probes directed against the MOR-1 clone produce distinct effects. Thus, MOR-1 AS ODN probes directed against exons 1 or 4 reduce morphine-, but not M6G-induced feeding, whereas probes directed against exons 2 or 3 reduce M6G-, but not morphine-induced feeding. AS ODN probes directed against different G-protein alpha-subunits differentially reduced morphine (G(ialpha2)) and M6G (G(ialpha1))-induced analgesia. The present study evaluated the ability of AS ODN probes directed against G-protein alpha-subunits to reduce feeding induced by morphine and M6G in rats. The AS ODN probes (25 microg, i.c.v.) were administered once 24 h prior to morphine (5 microg, i.c.v.) or M6G (250 ng) and spontaneous free feeding was assessed 1, 2 and 4 h thereafter. In agreement with analgesic studies, morphine-induced feeding was significantly reduced by the G(ialpha2) AS ODN probe. Morphine-induced feeding was unaffected by AS ODN probes directed against either G(ialpha1), G(ialpha3), G(oalpha), G(x/zalpha), G(qalpha) or a nonsense control probe, and was significantly enhanced by pretreatment with the G(salpha) probe. In contrast, M6G-induced feeding was significantly reduced by AS ODN probes directed against either G(ialpha1), G(ialpha3) or G(x/zalpha), whereas AS ODN probes targeting G(ialpha2), G(oalpha), G(salpha), G(qalpha) or a nonsense control probe were ineffective. When M6G-induced feeding was assessed at a dose (500 ng) which was sensitive to MOR-1 AS ODN effects, none of the G-protein alpha-subunit AS ODN probes were effective. These data indicate that morphine and M6G-induced feeding are mediated through different G-protein alpha-subunits, and provide further evidence for separate and distinct molecular mechanisms mediating these functional responses through different opioid receptors. This strongly suggests that M6G may act through a novel opioid receptor displaying a distinct pharmacological mechanism.
Silva
R M
RM
Department of Psychology and Neuropsychology Doctoral Sub-Program, Queens College, City University of New York, 65-30 Kissena Blvd., Flushing, NY 11367, USA.
Rossi
G C
GC
Mathis
J P
JP
Standifer
K M
KM
Pasternak
G W
GW
Bodnar
R J
RJ
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects*; D019204:GTP-Binding Proteins / Q000235:genetics*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009022:Morphine Derivatives / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D020033:Protein Isoforms / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D009022:Morphine Derivatives; D016376:Oligonucleotides, Antisense; D020033:Protein Isoforms; C035349:morphine-6-glucuronide; D009020:Morphine; D019204:GTP-Binding Proteins