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Opioid inhibition of Ih via adenylyl cyclase
1Vollum Institute, Oregon Health Sciences University, Portland 97201.
Abstract:
Opioids are coupled through G proteins to both ion channels and adenylyl cyclase. This study describes opioid modulation of the voltage-dependent cation channel, Ih, in cultured guinea pig nodose ganglion neurons. Forskolin, PGE2, and cAMP analogs shifted the voltage dependence of activation of Ih to more depolarized potentials and increased the inward current at -60 mV. Opioids had no effect on Ih alone, but reversed the effect of forskolin on Ih. This action of opioids was blocked by naloxone. Opioids had no effect on Ih in the presence of cAMP analogs, suggesting that modulation occurs at the level of adenylyl cyclase. The shift in the voltage dependence of Ih by agents that induce inflammation (i.e., PGE2) is one potential mechanism to mediate an increased excitability. Opioid inhibition of adenylyl cyclase and subsequent inhibition of Ih may be a mechanism by which opioids inhibit primary afferent excitability and relieve pain.
Insights
Opioid drugs modulate the Ih ion channel by inhibiting adenylyl cyclase, a key enzyme. This action may explain how opioids reduce neuronal excitability and relieve pain.
Area of Science:
- Neuroscience
- Molecular Pharmacology
Background:
- Opioids interact with G proteins, influencing ion channels and adenylyl cyclase.
- The voltage-dependent cation channel, Ih, plays a role in neuronal excitability.
Purpose of the Study:
- To investigate opioid modulation of the Ih channel in guinea pig nodose ganglion neurons.
- To elucidate the signaling pathways involved in opioid effects on Ih.
Main Methods:
- Cultured guinea pig nodose ganglion neurons were used.
- The effects of forskolin, PGE2, cAMP analogs, and opioids on Ih channel activity were measured.
- Naloxone was used to block opioid receptor activity.
Main Results:
- Forskolin, PGE2, and cAMP analogs depolarized the activation of Ih and increased inward current.
- Opioids reversed the forskolin-induced effects on Ih, an action blocked by naloxone.
- Opioids did not affect Ih in the presence of cAMP analogs, indicating modulation at the adenylyl cyclase level.
Conclusions:
- Opioid inhibition of adenylyl cyclase affects Ih channel function.
- This modulation may underlie the analgesic effects of opioids by reducing primary afferent excitability.