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Activation of mu opioid receptors inhibits transient high- and low-threshold Ca2+ currents, but spares a sustained
J E Schroeder1, P S Fischbach, D Zheng
1Department of Cell Biology and Physiology, Washington University, St. Louis, Missouri 63110.
Abstract:
Opioids and opiates decrease the duration of action potentials and the amount of neurotransmitter released from sensory neurons. The mu-type opioid receptor, the binding site for morphine, is thought to act exclusively on K+ channels. Here, we show that activation of the mu receptor inhibits Ca2+ channels in rat sensory neurons; the effect is blocked by a mu antagonist and is not mimicked by kappa or delta receptor agonists. Both low-threshold (T-type) and high-threshold Ca2+ currents are partially suppressed. omega-Conotoxin-sensitive and omega-conotoxin-insensitive, high-threshold Ca2+ currents are inhibited. The kinetic effect on high-threshold current is like that caused by diminished rest potential: the transient component is selectively lost, whereas the sustained component is spared.
Insights
Morphine, acting on mu-type opioid receptors, inhibits calcium (Ca2+) channels in rat sensory neurons. This discovery challenges the long-held belief that these receptors only affect potassium (K+) channels.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Opioids and opiates are known to reduce action potential duration and neurotransmitter release from sensory neurons.
- The mu-type opioid receptor, the primary target for morphine, was traditionally believed to exclusively modulate potassium (K+) channels.
Purpose of the Study:
- To investigate the direct effect of mu-type opioid receptor activation on ion channels in sensory neurons.
- To determine if mu-receptor activation influences calcium (Ca2+) channels, contrary to established understanding.
Main Methods:
- Utilized rat sensory neurons to study the effects of opioid receptor agonists and antagonists.
- Measured Ca2+ currents, including T-type and high-threshold currents, following mu-receptor activation.
- Differentiated effects using kappa and delta receptor agonists and specific antagonists.
Main Results:
- Activation of the mu-type opioid receptor was found to inhibit Ca2+ channels in sensory neurons.
- This inhibitory effect was specifically blocked by a mu-antagonist and not replicated by kappa or delta agonists.
- Both low-threshold (T-type) and high-threshold Ca2+ currents were partially suppressed, with a selective loss of the transient component in high-threshold currents.
Conclusions:
- Mu-type opioid receptor activation directly inhibits Ca2+ channels in sensory neurons, expanding known mechanisms of opioid action.
- This finding suggests a more complex role for mu-receptors beyond solely K+ channel modulation.
- The selective inhibition of Ca2+ current components offers new insights into opioid-induced analgesia and side effects.