Contribution of G inhibitory protein alpha subunits in paradoxical hyperalgesia elicited by exceedingly low doses of morphine in mice.

Although morphine, at higher doses, induces analgesia, it may also enhance sensitivity to pain at extremely low doses as shown in studies for testing an animal's sensitivity to pain. We used an antisense approach capable of selectively down-regulating in vivo G(i)(G inhibitory protein),G(o) and G(s) members of the G(α) sub-family protein subunits in order to establish if these proteins might be implicated in the effects induced by extremely low morphine doses on acute thermonociception.Mice pretreated with a morphine hyperalgesic dose (1μg/kg) were submitted to hot plate test after pre-treatment with antisense oligodeoxynucleotides (aODNs) targeting G(iα), G(oα) and G(sα) regulatory proteins. The association of G-protein (guanine nucleotide-binding regulatory protein) coupled receptors with G protein was investigated using co-immunoprecipitation procedure.The downregulation of the G(iα1-3) and G(oα1) proteins reversed the licking latency responses induced by 1μg/kg morphine administration toward the basal value whereas downregulation of the G(oα2) and G(sα) proteins did not significantly modify the hyperalgesic response.These results suggest that G inhibitory proteins play a role in the production of low dose evoked morphine hyperalgesia in mouse. Immunoprecipitation studies revealed that both μ opioid receptor (μOR) and α(2) adrenoreceptor (α(2) AR) are bound to G inhibitory proteins in hyperalgesic response to morphine extremely low dose. Both μOR and α(2) AR appear to be necessary for low morphine dose induced hyperalgesic response through G inhibitory proteins.