Handbook of experimental pharmacology
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Pain research has uncovered important neuronal mechanisms that underlie clinically relevant pain states such as inflammatory and neuropathic pain. Importantly, both the peripheral and the central nociceptive system contribute significantly to the generation of pain upon inflammation and nerve injury. Peripheral nociceptors are sensitized during inflammation, and peripheral nerve fibres develop ectopic discharges upon nerve injury or disease. ⋯ The spinal processes are significantly influenced by brain stem circuits that inhibit or facilitate spinal nociceptive processing. Numerous mechanisms are involved in peripheral and central nociceptive processes including rapid functional changes of signalling and long-term regulatory changes such as up-regulation of mediator/receptor systems. Conscious pain is generated by thalamocortical networks that produce both sensory discriminative and affective components of the pain response.
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Convincing evidence from preclinical studies demonstrates that cannabinoids can reduce pain responses in a range of inflammatory and neuropathic pain models. The anatomical and functional data reveal cannabinoid receptor-mediated analgesic actions operating at sites concerned with the transmission and processing of nociceptive signals in brain, spinal cord and the periphery. ⋯ In contrast, the clinical effectiveness of cannabinoids as analgesics is less clear. Progress in this area requires the development of cannabinoids with a more favourable therapeutic index than those currently available for human use, and the testing of their efficacy and side-effects in high-quality clinical trials.
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Handb Exp Pharmacol · Jan 2007
ReviewPhospholipase C-coupled receptors and activation of TRPC channels.
The canonical transient receptor potential (TRPC) cation channels are mammalian homologs of the photoreceptor channel TRP in Drosophila melanogaster. All seven TRPCs (TRPC1 through TRPC7) can be activated through Gq/11 receptors or receptor tyrosine kinase (RTK) by mechanisms downstream of phospholipase C. ⋯ TRPC channels have been proposed to be activated by a variety of signals including store depletion, membrane lipids, and vesicular insertion into the plasma membrane. Here we discuss recent developments in the mode of activation as well as the pharmacological and electrophysiological properties of this important and ubiquitous family of cation channels.
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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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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.