Associate editor: M. EndohMolecular mechanisms of neuropathic pain–phenotypic switch and initiation mechanisms
Introduction
Advances in molecular biological techniques and the subsequent discovery of specific molecules involved in pain production has clearly contributed to a better understanding of pain (Furst, 1999, Scholz & Woolf, 2002, Ueda & Rashid, 2003). Pain has been broadly categorized into 3 groups: nociceptive (or physiological), inflammatory, and neuropathic pain (Scholz & Woolf, 2002). Inflammatory pain results from tissue damage and is reversible when the underlying cause has been rectified. On the other hand, neuropathic pain results from damage to components of the nervous system such as primary afferent nerves, spinal cord, and central nervous system (CNS) regions. As the onset of neuropathic pain may be delayed after a nerve injury, pain may still be present after healing is complete. This makes proper diagnosis and early treatment difficult. Moreover, neuropathic pain commonly occurs as a secondary symptom in diseases like diabetes, cancer, and herpes zoster infection; it may also occur with treatments such as chemotherapeutics or cytotoxic drugs (Woolf & Mannion, 1999, Bridges et al., 2001, Sah et al., 2003). The presence of neuropathic pain is often characterized by stimulus-independent persistent pain or abnormal sensory perception of pain such as allodynia (pain perception on exposure to innocuous tactile stimuli) and hyperalgesia (exaggerated pain sensations as a result of exposure to mildly noxious stimuli; Woolf & Mannion, 1999, Bridges et al., 2001).
The pathomechanisms of different types of pain have been studied with the aim of developing new pharmacotherapies for specific pain types. As pain is a subjective sensation, it is difficult to evaluate correctly in clinical trials. Most of the currently used analgesic drugs fall into the categories of opioids and nonsteroidal antiinflammatory drugs (NSAIDS) such as COX-2 inhibitors, which are often used clinically for nociceptive and inflammatory pain, but not for neuropathic pain. The management of neuropathic pain is still a major challenge to clinicians because of its unresponsiveness to most common painkillers (MacFarlane et al., 1997). Even the opioid drugs are considered to be less effective for neuropathic pain than nociceptive or inflammatory pain (Ossipov et al., 1995, Idanpaan-Heikkila et al., 1997). The current pharmacotherapy of neuropathic pain includes the use of unconventional agents such as topical capsaicin (or capsaicin cream/ointment), tricyclic antidepressants, certain anticonvulsants, and in some cases, opioids (Low et al., 1995, Sawynok, 2003); however, the use of these agents is associated with suboptimal therapeutic efficacies and/or side effects. Thus, there has been a continuing search for novel drug molecules to alleviate neuropathic pain. The search for such molecules has been impeded by the poor understanding of the molecular mechanism of neuropathic pain. This review will focus on recent findings based on new experimental strategies that will help elucidate the molecular mechanisms of neuropathic pain.
Section snippets
Nociception tests for the study of neuropathic pain
Pain is a sensory mechanism that warns us of imminent tissue damage. Nociceptors located at the terminals of thinly myelinated Aδ-fiber or unmyelinated C-fiber primary afferent neurons transduce noxious chemical, mechanical, or thermal stimuli into depolarizing currents that ultimately induce action potentials (Hunt & Mantyh, 2001). These action potentials are then conducted to higher centers in the central nervous system (CNS) through the release of neurotransmitters and are accompanied by a
Animal models of neuropathic pain
The study of neuropathic pain mechanisms is largely based on animal models. Although these models have weak points, they provide important clues in understanding the underlying pathophysiology of neuropathic pain in humans. One major drawback is the lack of verbal communication; thus, the evaluation of pain in these models is based on empirical behavioral responses. Neuropathic pain in experimental animal models is measured as allodynia or hyperalgesia, where the normally innocuous or mildly
Molecular basis of mechanisms for neuropathic pain
Neuropathic pain occurs as a consequence of complex sensory dysfunction and may differ depending on the type of insult and the individual patient. Furthermore, due to the dynamic nature of the pain system, the signs and symptoms of neuropathic pain changes over time. Injury to a peripheral nerve causes functional and biochemical changes not only at the site of injury, but also to other parts of the affected nerve and in due course to higher order neurons in the spinal cord and brain (Bridges et
Lysophosphatidic acid as an initiator of neuropathic pain
Lysophosphatidic acid (LPA) is one of several lipid metabolites released after tissue injury (Schumacher et al., 1979, Eichholtz et al., 1993) and from some cancer cells (Mills & Moolenaar, 2003).This would therefore make it an attractive candidate as a signaling molecule in the development of neuropathic pain. LPA is a small phospholipid that has well-documented signaling properties and activates cognate G-protein coupled receptors (LPA1–4; Fukushima et al., 2001, Ishii et al., 2004). Although
Conclusion
I have presented an overview of the mechanisms of neuropathic pain, which includes many complex processes. One of the hypotheses I present is the phenotypic switch in the nociceptive transmission, in which various pain-related molecules are down-regulated in unmyelinated C-fibers but up-regulated in myelinated A-fibers. A further hypothesis is that LPA plays an important role in the initiation of neuropathic pain and its underlying mechanisms, including demyelination and the up-regulation of
Acknowledgments
I thank Misaki Matsumoto for kind help in preparing this manuscript. This study was supported by Special Coordination Funds of the Science and Technology Agency of the Japanese Government and by a Grant-in-Aid from the Ministry of Education, Science, Culture, and Sports of Japan and Human Frontier Science Program.
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