Endogenous opioid neurotransmitters in the spinal cord and brain constitute a pain inhibitory system; they are activated by nociceptive and other inputs (including treatments such as transcutaneous nerve stimulation, and acupuncuture) and mediate their effects through specific receptors. Activation of opioid receptors prevents the release of substance P (a neurotransmitter and local hormone involved in pain transmission) with the result that pain transmission is inhibited. Several types of receptor have been recognised, principally: (4, (mu), 8 (delta) and k (kappa) receptors for which the endogenous ligands respectively are: endomorphins, met-encephalin and dynorphins.
Synthetic opioids produce analgesia by simulating the body's natural opioids and the existence of different types of receptor explains their varying patterns of actions. Definition of these receptors and their subdivisions offers hope for the design of new selective high-efficacy analgesics free from the disadvantages of the existing opioids.
Naloxone, the competitive opioid antagonist, binds to and blocks all opioid receptors but exerts no activating effect. Naloxone has particularly high affinity for the (i-receptor; it worsens (dental) pain, an effect that may be explained by blocking access of endogenous opioids to their receptor(s).9 It does not induce hyperalgesia or spontaneous pain because the opioid paths are quiescent until activated by nociceptive and other afferent input.
In addition to these opioid mechanisms, non-opioid mediated pathways, e.g. serotonin, are important in pain. There is suggestion that opioid mechanisms are more important in acute severe pain, and nonopioid mechanisms in chronic pain, and that this may be relevant to choice of drugs.
NSAIDs. When a tissue is injured (from any cause), or even merely stimulated, prostaglandin synthesis in that tissue increases. Prostaglandins have two major actions: they are mediators of inflammation and they also sensitise nerve endings, lowering their threshold of response to stimuli, mechanical (the tenderness of inflammation) and chemical, allowing the other mediators of inflammation, e.g. histamine, serotonin, bradykinin, to intensify the activation of the sensory endings.
Plainly, a drug that prevents the synthesis of prostaglandins is likely to be effective in relieving pain due to inflammation of any kind, and this is indeed how aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) act. This discovery was made in 1971, aspirin having been extensively
9 Naloxone also appears to cause pyrovats (practitioners of religious firewalking ceremonies) to quicken their pace over the hot coals.
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