Sign-reversal during persistent activation in mu-opioid signal transduction.
A concept of signal transduction in biological systems specifies that any instantaneous input is appreciated by its departure from the moving average of past activity. The concept provides an adequate account of the occurrence of both the one-directional (e.g. analgesic) effects induced by opioid receptor activation, and of the contra-directional (e.g. hyperalgesic) effects that can be observed when activation is discontinued. Following this transduction concept, the numerical simulations reported here revealed, remarkably, that under some parametric conditions, the input's effect may reverse even as input is maintained at a constant magnitude. In in vitro conditions that are proximal to the signal transduction that occurs when an opioid agonist binds to the G-protein coupled opioid receptor, the effects of opioid receptor activation were monitored by measuring time-dependent Ca(2+) responses in CHO-K1 cells transfected with a mu-opioid receptor and G(alpha 15) protein. The results indicate morphine to produce an initial increase in intracellular Ca(2+) concentration followed by a decrease below basal level. The occurrence of a sign-reversal was confirmed in native conditions of receptor-to-G protein coupling; the continuous in vivo infusion over a 2-week period of 0.31 mg rat(-1)day(-1) of fentanyl initially caused an increase of the mechanical threshold to induce a pain response (i.e. analgesia) that was followed by a decrease (i.e. hyperalgesia). The findings indicate that with opioid signaling systems, transduction mechanisms operate that may cause the sign of the effect to reverse not only when activation is discontinued but also whilst it is maintained at a constant magnitude.
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D000704:Analysis of Variance; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002477:Cells / Q000378:metabolism*; D003198:Computer Simulation; D006224:Cricetinae; D005283:Fentanyl / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D009020:Morphine / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D012044:Regression Analysis; D015398:Signal Transduction / Q000502:physiology*
D009294:Narcotics; D017450:Receptors, Opioid, mu; D009020:Morphine; D002118:Calcium; D005283:Fentanyl