Analgesia involved

The best-understood sites of action of morphine are at spinal and brainstem/ midbrain loci, producing both the wanted and unwanted effects of the opioid. The spinal actions of opioids and their mechanisms of analgesia involve (1) reduced transmitter release from nociceptive C-fibres so that spinal neurons are less excited by incoming painful messages, and (2) postsynaptic inhibitions of neurons conveying information from the spinal cord to the brain. This dual action of opioids can result in a... 

All opioids produce their effect by activating one or more of the three types of receptors. Thus analgesia involves the activation of the mu receptors that are located mainly at supraspinal sites and kappa receptors in the spinal cord delta receptors may also be involved but their relative contribution is unclear. Nevertheless, the actions of the opioids on these receptors is complex, as there is evidence that the same substance may act as a full agonist, or as an antagonist at different sites within the brain. 

Numerous neuropeptides are beheved to be involved with the transmission or inhibition of pain, and the hope is to utilize this approach as a strategy to induce analgesia. Substance P is reported to be a transmitter of nociceptive impulses (39), and therefore antagonists should be analgesic. Capsaicin [404-86-4], C2gH2yN02, is known to deplete substance P and cause analgesia (40), but its side effects are intolerable. Antagonists to bradykinin [58-82-2], a substance known to induce pain (41), have shown some success in preclinical trials. 

It is important to point out that some types of placebo analgesia appear to be insensitive to naloxone, thus suggesting that neuromodulators other than opioids can be involved in some circumstances. For example, if a placebo is given after repeated administrations (preconditioning) of the non-opioid painkiller ketorolac, the placebo analgesic response is not blocked by naloxone. 

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. 

The mainstay of treatment for vaso-occlusive crisis includes hydration and analgesia (see Table 65-7). Pain may involve the extremities, back, chest, and abdomen. Patients with mild pain crises may be treated as outpatients with rest, warm compresses to the affected (painful) area, increased fluid intake, and oral analgesia. Patients with moderate to severe crises should be hospitalized. Infection should be ruled out because it may trigger a pain crisis, and any patient presenting with fever or critical illness should be started on empirical broad-spectrum antibiotics. Patients who are anemic should be transfused to their baseline. Intravenous or oral fluids at 1.5 times maintenance is recommended. Close monitoring of the patient s fluid status is important to avoid overhydration, which can lead to ACS, volume overload, or heart failure.6,27... 

Morphine may be administered orally, intravenously, or epidurally. An advantage of epidural administration is that it provides effective analgesia while minimizing the central depressant effects associated with systemic administration. The mechanism of action with the epidural route of administration involves opioid receptors on the cell bodies of first-order sensory neurons in the dorsal root ganglia as well as their axon terminals in the dorsal hom. Stimulation of these receptors inhibits release of substance P and interrupts transmission of the pain signal to the second-order sensory neuron. 

Recent antisense studies have shown that knock down of Gi2 in mice-blocked morphine-induced analgesia, suggesting that morphine binds to fi receptors to activate G 2 to modulate neuronal circuits involved in analgesia [68, 84]. Sufentanil-induced analgesia was not diminished by Gi2 knock down suggesting that a different G protein mediated its behavioral effects [84]. 

There is also evidence for cholinergic involvement in caffeine analgesia (Ghelardini et al. 1997). The muscarinic antagonists atropine and pirenzepine, and the choline uptake inhibitor hemicholinium-3 prevent caffeine analgesia. In contrast, it was unaffected by an opioid antagonist (naloxone) or a tyrosine hydroxylase inhibitor (o-methyl-p-tyrosine). 

The cellular mechanism of cannabinoid analgesia is uncertain. Although cAMP and adenylate cyclase mediate other effects of cannabinoids, they do not appear to be involved in cannabinoid-induced analgesia (Cook et al. 1995). Instead, other mechanisms such as cannabinoid receptor-coupled calcium or potassium channels may be responsible. 

Kauppila et al. 1992). The synergistic interaction between cocaine and opioid analgesia likely involves noradrenergic mechanisms, supraspinal ju and 5 receptors, and spinal ju receptors (Misra et al. 1987 Sierra et al. 1992). 

Della Bella D, Carenzi A, Frigeni V, Reggiani A, Zambon A. (1985). Involvement of monoaminergic and peptidergic components in cathinone-induced analgesia. EurJ Pharmacol. 114(2) 231-34. Desjardins GC, Brawer JR, Beaudet A. (1990). Distribution of mu, delta, and kappa opioid receptors in the hypothalamus of the rat. Brain Res. 536(1-2) 114-23. 

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