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Stimulatory effects of opioids on transmitter release and possible cellular mechanisms: overview and original results
Abstract:
Opiates and opioid peptides carry out their regulatory effects mainly by inhibiting neuronal activity. At the cellular level, opioids block voltage-dependent calcium channels, activate potassium channels and inhibit adenylate cyclase, thus reducing neurotransmitter release. An increasing body of evidence indicates an additional opposite, stimulatory activity of opioids. The present review summarizes the potentiating effects of opioids on transmitter release and the possible cellular events underlying this potentiation: elevation of cytosolic calcium level (by either activating Ca2+ influx or mobilizing intracellular stores), blockage of K+ channels and stimulation of adenylate cyclase. Biochemical, pharmacological and molecular biology studies suggest several molecular mechanisms of the bimodal activity of opioids, including the coupling of opioid receptors to various GTP-binding proteins, the involvement of different subunits of these proteins, and the activation of several intracellular signal transduction pathways. Among the many experimental preparations used to study the bimodal opioid activity, the SK-N-SH neuroblastoma cell line is presented here as a suitable model for studying the complete chain of events leading from binding to receptors down to regulation of transmitter release, and for elucidating the molecular mechanism involved in the stimulatory effects of opioid agonists.
Insights
Opioids exhibit dual regulatory effects, primarily inhibiting neuronal activity but also stimulating neurotransmitter release. This review explores the molecular mechanisms behind this bimodal opioid activity.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Opioid peptides and opiates traditionally inhibit neuronal activity by modulating ion channels and adenylate cyclase.
- Emerging evidence reveals a paradoxical stimulatory role for opioids in neurotransmitter release.
Purpose of the Study:
- To review the potentiating effects of opioids on neurotransmitter release.
- To elucidate the cellular and molecular mechanisms underlying the stimulatory actions of opioids.
Main Methods:
- Review of biochemical, pharmacological, and molecular biology studies.
- Utilizing the SK-N-SH neuroblastoma cell line as a model system.
Main Results:
- Opioid stimulation involves elevated cytosolic calcium, K+ channel blockade, and adenylate cyclase activation.
- Molecular mechanisms include coupling of opioid receptors to GTP-binding proteins and activation of intracellular signaling pathways.
Conclusions:
- Opioids possess bimodal activity, inhibiting and stimulating neuronal function.
- The SK-N-SH cell line is a valuable model for dissecting the stimulatory effects of opioid agonists.