Central inhibitory systems

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The role of inhibitory systems is important in the control of events following C-fiber stimulation. Opioids are the major inhibitory controls on pain and all clinically used opioid drugs act on the receptor, the receptor for morphine which is thought to be responsible for both the analgesic and adverse effects of morphine [70]. The actions of clinically used opioids can now be explained in terms of their acting as agonists at one of the four opioid receptors found in the brain, spinal cord and peripheral nervous system. All opioid receptors are inhibitory. The receptors are for the endogenous opioid peptides that function as transmitters in the nervous system. Like all other peptides, they are synthesized as large inactive precursors in the neuronal cell body and transported to the terminal, with processing en route yielding the active fragment which is then released into the synapse and activates the appropriate receptors. Morphine activates opioid receptors to a much greater extent than the opioid peptides and so produces profound analgesia.

The opioid receptors are found on postsynaptic sites but presynaptic locations predominate so that activation of the receptors can control the release of a number of neurotransmitters. The endogenous pep-tides are rapidly degraded so that nonpeptide agonists are needed. Side effects are due to the peripheral and central receptors whereas the analgesic effects are due to the interaction of opioid with central receptors. The degree of analgesia can be limited by the side effects. All clincially important opioids act on the mu receptor and hopes for other opioids acting on the other opioid receptors have not yet been fulfilled.

p Receptors are located in the periphery, where their transportation from the DRG is upregulated following inflammation [71], and at pre- and post-synaptic sites in the spinal cord and in the brain. The actions of opioids are best understood in the DH of the spinal cord, where their analgesic mechanisms involve reduced transmitter release from nociceptive C-fibers following noxious stimulation [72], and postsynaptic inhibitions resulting from K+ hyperpolarization of projection neurones conveying information from the spinal cord to the brain. The opioid receptors in the spinal cord are predominantly of the and 8 types and are found in the C-fiber terminal zone (the substantia gelatinosa) in the superficial dorsal horn. Up to 75% of the opioid receptors are found presynaptically on the C-fiber terminals and when activated, inhibit neurotransmitter release. Their opening of potassium channels will reduce calcium flux. The remaining postsynaptic receptors hyperpolarize and so inhibit projection neurones and interneurones; the net result is further inhibition of the C-fiber induced activity. This spinal action of opioids 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 opioid receptors in the brain and periphery. Complete C-fiber inhibition can be produced and so complete analgesia can be achieved but opioids do not always act so effectively when the pain arises from nerve damage. Reasons for this are suspected to be excessive transmitter release and spinal NMDA-mediated activity which are hard to inhibit.

There are other important sites of opioid actions located in the 5HT and noradrenergic nuclei of the brainstem and midbrain, including the raphe nuclei (RVM), the periaqueductal gray matter (PAG) and the locus coeruleus. These areas of the brain are important in sleep, anxiety and fear and explain how these functions interact with and are altered by pain. Opioid receptors in these zones, when activated, alter the level of activity in descending pathways from these zones to the spinal cord that in turn reduces activity of spinal cord neurones. The relative roles of the 5HT receptors in the spinal cord are unknown but the spinal target for noradrenaline (NA) released from descending pathways is a2 receptors which have similar actions and distribution to the opioid receptors. Sedation and hypotension with a2 agonists presently limit their use as analgesics but they are useful veterinary drugs.

Most of the data concerning morphine analgesia have been derived from studies of patients with cancer pain, since its therapeutic potential for the treatment of neuropathic pain has been limited [73]. However, opioid therapy for chronic noncancer pain (CNCP) is now becoming more acceptable where long-term consumption can be therapeutically beneficial [74, 75]. Moreover, methadone, normally associated with the treatment of opioid addiction, may provide an appropriate replacement when side effects have limited dose escalation [76]. Tramadol, which displays both serotonergic and opioidergic mechanisms, has proved effective in the treatment of painful diabetic peripheral neuropathy [77] and relieved ongoing pain and reduced allodynia in patients with polyneuropa-thy [78], and offers a treatment option with lower abuse liability [79].

The ORL1 receptor (also known as nociceptin, orphanin FQ or NOP receptor) is structurally related to opioid receptors but resistant to classic opioid agonists such as morphine [80]. The endogenous lig-and for ORL1 receptors, nociceptin, is thought to be important in spinal nociceptive transmission [81- 83] and displays antinociceptive effects in animal models of neuropathic and inflammatory pain [84, 85]. Recently, a likely mechanism has been proposed involving ORL1 receptor-mediated internalization of calcium channels leading to decreased neuronal excitability [86].

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