Spinal Opiate Analgesia

Opioids act in the brain and within the dorsal horn of the spinal cord, where their actions are better understood. The actions of opioids important for analgesia and their side-effects involve pre- and postsynaptic effects: (1) reduced transmitter release from nerve terminals so that neurons are less excited by excitatory transmitters, and (2) direct inhibitions of neuronal firing so that the information flow from the neuron is reduced but also inhibitions of inhibitory neurons leading to disinhibition. This dual action of opioids can result in a total block of sensory inputs as they arrive in the spinal cord (Fig. 21.5). Thus any new drug would have to equal this dual action in controlling both transmitter release and neuronal firing.

C-fibre stimulation will release a number of transmitters in the spinal cord including substance P, CGRP, glutamate and aspartate. By actions on their receptors the peptides produce slow depolarising responses of dorsal horn neurons which in concert with the fast AMPA and delayed NMDA receptor-mediated depolarisations produced by the excitatory amino-acids activate ascending, local and motoneurons to cause both the sensation of pain and the withdrawal reflex to the stimulus (see Fig. 21.4). There is good reason to believe that the spinal processing of pain is highly plastic and can be altered in different pain states.

The opiate receptors in the spinal cord are predominantly of the mu and delta type and are found in the C-fibre terminal zone (the substantia gelatinosa) in the superficial dorsal horn. Considerable numbers of ORL-1 receptors are also found in this area. Up to 75% of the opiate receptors are found presynaptically on the C-fibre terminals and when activated inhibit neurotransmitter release. The opening of potassium channels will reduce calcium flux in the terminal and so there will be a resultant decrease in

PRESYNAPTIC - TERMINAL

POSTSYNAPTIC - NEURON

PRESYNAPTIC - TERMINAL

calcium

calcium mu opioid recept potassium

Figure 21.5 Mechanisms of opioid analgesia at the spinal level. Action potentials in nociceptive afferent fibres invade the terminal and by opening calcium channels (L, N and P-type) cause the release of glutamate and peptides that further transmit pain subsequent to activation of their postsynaptic receptors. Presynaptic opioid receptor activation (mu- and delta-mediated effects have been most clearly shown) opens potassium channels which hyperpolarise the terminal, so reducing transmitter release and inhibiting the postsynaptic neuron calcium glutamate & peptid delta opioid recepl calcium mu opioid recept potassium calcium char LNP

glutamate & peptid delta opioid recepl calcium char LNP

Figure 21.5 Mechanisms of opioid analgesia at the spinal level. Action potentials in nociceptive afferent fibres invade the terminal and by opening calcium channels (L, N and P-type) cause the release of glutamate and peptides that further transmit pain subsequent to activation of their postsynaptic receptors. Presynaptic opioid receptor activation (mu- and delta-mediated effects have been most clearly shown) opens potassium channels which hyperpolarise the terminal, so reducing transmitter release and inhibiting the postsynaptic neuron release of all the transmitters in the C-fibres. The remaining postsynaptic receptors appear to hyperpolarise the dendrites of projection neurons and interneurons and disinhibit inhibitory interneurons; the net result is further inhibition of the C-fibre-induced activity. This spinal action of opiates can be targeted by using the intrathecal or epidural routes of administration which have an advantage over systemic application of avoiding the side-effects mediated by opiate receptors in the brain and periphery.

Complete C-fibre inhibitions can be produced under normal conditions but opiates do not always produce a complete analgesia in some clinical situations, especially when the pain arises from nerve damage. Reasons for this are suspected to be excessive NMDA-mediated activity which is hard to inhibit and the mobilisation of cholecysto-kinin in the spinal cord which can act as a physiological antagonist of opiate actions. The idea that pre-emptive analgesia aids post-operative pain relief by preventing the pain-induced activation of these systems is becoming popular.

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