Handbook of experimental pharmacology
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Handb Exp Pharmacol · Jan 2007
ReviewProtein kinases as potential targets for the treatment of pathological pain.
Pathological pain or clinical pain refers to tissue injury-induced inflammatory pain and nerve injury-induced neuropathic pain and is often chronic. Pathological pain is an expression of neural plasticity that occurs both in the peripheral nervous system (e.g., primary sensory nociceptors), termed peripheral sensitization, and in the central nervous system (e.g., dorsal horn and brain neurons), termed central sensitization. Our insufficient understanding of mechanisms underlying the induction and maintenance of injury-induced neuronal plasticity hinders successful treatment for pathological pain. ⋯ MAPKs are also activated in spinal glial cells (microglia and astrocytes) after injuries, leading to the synthesis of inflammatory mediators/neuroactive substances that act on nociceptive neurons, enhancing and prolonging pain sensitization. Inhibition of multiple kinases has been shown to attenuate inflammatory and neuropathic pain in different animal models. Development of specific inhibitors for protein kinases to target neurons and glial cells will shed light on the development of new therapies for debilitating chronic pain.
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The discovery of the endogenous systems of analgesia has produced a large amount of research aimed at investigating their biochemical and neurophysiological mechanisms and their neuroanatomical localization. Nevertheless, the neurobiological acquisitions on these mechanisms have not been paralleled by behavioural correlates in humans--in other words, by the understanding of when and how these endogenous mechanisms of analgesia are activated. ⋯ By contrast, today the placebo analgesic effect represents one of the best-described situations in which this endogenous opioid network is naturally activated in humans. Therefore, not only is placebo research helpful towards improving clinical trial design and medical practice, but it also provides us with a better understanding of the endogenous mechanisms of analgesia.
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Opioids are the most effective and widely used drugs in the treatment of severe pain. They act through G protein-coupled receptors. Four families of endogenous ligands (opioid peptides) are known. ⋯ Three classes of opioid receptors (mu, delta, kappa) have been identified. Multiple pathways ofopioid receptor signaling (e.g., G(i/o) coupling, cAMP inhibition, Ca++ channel inhibition) have been described. The differential regulation of effectors, preclinical pharmacology, clinical applications, and side effects will be reviewed in this chapter.
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Handb Exp Pharmacol · Jan 2007
ReviewAntipyretic analgesics: nonsteroidal antiinflammatory drugs, selective COX-2 inhibitors, paracetamol and pyrazolinones.
Antipyretic analgesics are a group of heterogeneous substances including acidic (nonsteroidal antiinflammatory drugs, NSAIDs) and nonacidic (paracetamol, pyrazolinones) drugs. Moreover, various selective cyclooxygenase-2 (COX-2) inhibitors with improved gastrointestinal tolerability as compared with conventional NSAIDs have been established for symptomatic pain treatment in recent years. The present review summarizes the pharmacology of all of these drugs with particular emphasis on their rational use based on the diverse pharmacokinetic characteristics and adverse drug reaction profiles. Referring to the current debate, potential mechanisms underlying cardiovascular side effects associated with long-term use of COX inhibitors are discussed.
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Damage to a nerve should only lead to sensory loss. While this is common, the incidence of spontaneous pain, allodynia and hyperalgesia indicate marked changes in the nervous system that are possible compensations for the loss of normal function that arises from the sensory loss. Neuropathic pain arises from changes in the damaged nerve which then alter function in the spinal cord and the brain and lead to plasticity in areas adjacent to those directly influenced by the neuropathy. ⋯ In addition to these spinal mechanisms of hyperexcitability, spinal cells participate in a spinal-supraspinal loop that involves parts of the brain involved in affective responses to pain but also engages descending excitatory and inhibitory systems that use the monoamines. These pathways become more active after nerve injury and are the site of action of anti-depressants. This chapter reviews the evidence and mechanisms of drugs, both anti-depressants and anti-convulsants, that are believed to be effective in pain control, with a major emphasis on the neuropathic state.