Effect of Opioids on CNS Synapses

Opioids basically exert their analgesic effects by inhibiting synaptic transmission in key pain pathways in the spinal cord and brain. This inhibitory effect is mediated by opioid receptors that are located on both presynaptic and postsynaptic membranes of pain-mediating synapses (Fig. 14—2). In the spinal cord, for example, receptors are located on the presynaptic terminals of primary (first-order) nociceptive afferents, and when bound by opioids, they directly decrease the release of pain-mediating transmitters such as substance P.35,38 Opioid drug-receptor interactions also take place on the postsynaptic membrane of the secondary afferent neuron—that is, the second-order nociceptive afferent neuron in the spinal cord.19,33 When stimulated, these receptors also inhibit pain transmission by hyperpolarizing the postsynaptic neuron.19 

Opioids therefore inhibit synaptic transmission by decreasing neurotransmitter release from the presynaptic terminal and by decreasing excitable (hyperpolarizing) postsynaptic neurons within key pain pathways in the spinal cord and brain. Again, these synaptic effects can either limit the transmission of painful stim- 

FIGURE 14-2 Schematic representation of how opioid analgesics may impair synaptic transmission in pain-mediating pathways. The drug binds to specific opioid receptors on the presynaptic and postsynaptic membranes. 

As described in Chapter 4, regulatory G proteins act as an intermediate link between receptor activation and the intracellular effector mechanism that ultimately causes a change in cellular activity. In the case of opioid receptors, these G proteins interact with three primary cellular effectors calcium channels, potassium channels, and the adenyl cyclase enzyme.27 At the presynaptic terminal, stimulation of opioid receptors activates G proteins that in turn inhibit the opening of calcium channels on the nerve membrane.65 Decreased calcium entry into the presynaptic terminal causes decreased neurotransmitter release because calcium influx mediates transmitter release at a chemical synapse. At the postsynaptic neuron, opioid receptors are linked via G proteins to potassium channels, and 

SECTION 4 Drugs Used to Treat Pain and Inflammation 

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