Abstract
Calcium ions are widely recognized to play a fundamental role in the regulation of several biological processes. Transient changes in cytoplasmic calcium ion concentration represent a key step for neurotransmitter release and the modulation of cell membrane excitability. Evidence has accumulated for the involvement of calcium ions also in nociception and antinociception, including the analgesic effects produced by opioids. The combination of opioids with drugs able to interfere with calcium ion functions in neurons has been pointed out as a useful alternative for safer clinical pain management. Alternatively, drugs that reduce the flux of calcium ions into neurons have been indicated as analgesic alternatives to opioids. This article reviews the manners by which calcium ions penetrate cell membranes and the changes in these mechanisms caused by opioids and calcium antagonists regarding nociceptive and antinociceptive events.
Highlights
During the past few years evidence has accumulated about the property of opioid agonists to modify membrane excitability and intracellular signaling by direct or indirect modification of the transmembrane flux of calcium ions (Ca2+)
Ca2+ influx occurs via three main pathways: the voltageoperated calcium channels (VOCC), which are opened by membrane depolarization, the ligand-gated nonspecific calcium channels, and the receptor-activated calcium channels (RACC)
Flunarizine had a mixed opioid activity, acting as an agonist on μreceptors and as an antagonist on d- and kreceptor subtypes. It verapamil or nifedipine was less effective than it Quin-2 in reducing the 2nd phase of the rat response to formalin, results that were interpreted as evidence that Ca2+ influx through channels other than phenylalkylamine- and dihydropyridine-sensitive VOCC may be involved in the process [7]
Summary
During the past few years evidence has accumulated about the property of opioid agonists to modify membrane excitability and intracellular signaling by direct or indirect modification of the transmembrane flux of calcium ions (Ca2+). A transient increase in cytoplasmic Ca2+ concentration represents a key step for neurotransmitter release and the modulation of cell membrane excitability, and depends on the passage of Ca2+ through membrane channels, transport by ion pumps, or release of Ca2+ from internal stores (for a review, see Ref. 1). Ca2+ influx occurs via three main pathways (for a review, see Ref. 2): the voltageoperated calcium channels (VOCC), which are opened by membrane depolarization, the ligand-gated nonspecific calcium channels, and the receptor-activated calcium channels (RACC). Two main types of RACC have been described: the store-operated, or capacitative, calcium channels and the intracellular messenger-activated nonselective channels. The VOCC were classified into low-threshold (or T-type) and high-threshold activated channels.
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