Hypertolerance to morphine in G(z alpha)-deficient mice.
Our laboratory has generated a mouse deficient in the alpha (alpha) subunit of the G protein, G(z), (G(z alpha)) gene and we have examined the involvement of G(z alpha) in spinal and supraspinal analgesia and tolerance mechanisms. Spinal analgesia was tested by the response times to heat or cold tail flick times in a water bath at 50 degrees C or -5 degrees C and supraspinal analgesia was tested by the times for paw licking and jumping from a plate at 52 degrees C or 0.5 degrees C. Tolerance to morphine was induced in wild type and G(z alpha)-deficient mice over a 5 day period and the behavioral tests were performed daily. The tail flick reaction times to both hot and cold stimuli did not differ between the wild type and G(z alpha)-deficient mice. Analysis of the reaction times from the hot and cold plate tests showed the G(z alpha)-deficient mice developed tolerance to morphine to a greater degree and at a faster rate than wild type mice. Opioid binding assays were performed on synaptic membranes prepared from naive and morphine tolerant wild type and G(z alpha)-deficient brains. No changes in the affinity of morphine for its receptor or in the density of mu and delta opioid receptors were found between the two groups of mice in the naive or morphine tolerant state. This indicates that the absence of G(z alpha) does not affect opioid receptor affinity or receptor up or down regulation. Our results suggest that the presence of G(z alpha) delays the development of morphine tolerance and represents a possible therapeutic target for improving the clinical use of morphine.
Hendry
I A
IA
Division of Neuroscience, John Curtin School of Medical Research, Australian National University, GPO Box 334, ACT 2601, Canberra, Australia. ian.henry@anu.edu.au
Kelleher
K L
KL
Bartlett
S E
SE
Leck
K J
KJ
Reynolds
A J
AJ
Heydon
K
K
Mellick
A
A
Megirian
D
D
Matthaei
K I
KI
D000698:Analgesia; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D003080:Cold Temperature; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000235:genetics*; D044385:GTP-Binding Protein alpha Subunits; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000032:analysis; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000032:analysis; D019204:GTP-Binding Proteins / Q000032:analysis; D020962:Heterotrimeric GTP-Binding Proteins / Q000032:analysis / Q000235:genetics*; D006358:Hot Temperature; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D017288:Pain Threshold / Q000187:drug effects; D011869:Radioligand Assay; D011957:Receptors, Opioid / Q000032:analysis; D013116:Spinal Cord / Q000737:chemistry / Q000187:drug effects; D013623:Tail
D000701:Analgesics, Opioid; D044385:GTP-Binding Protein alpha Subunits; C490964:Gnaz protein, mouse; D011957:Receptors, Opioid; D009020:Morphine; D019204:GTP-Binding Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019205:GTP-Binding Protein alpha Subunits, Gs; D020962:Heterotrimeric GTP-Binding Proteins