Research on pain is focused on neurobiology studies concerning neuronal plasticity development, nocicep-tors molecular identity, signaling mechanisms, ionic channels involved in the generation, modulation and propagation of action potentials in all type of excitable cells. All the findings open the possibility for developing new therapeutic treatment. The interest of researchers for receptors, neurotrans-mitters, second messengers, transcription factors involved in neuronal processing, in spinal cord and in cortical areas, increased dramatically. There are evi-dences clarifying the origin of chronic pain. Now it is well known the existence of two different kind of persistent chronic pain: nociceptive/inflamma-tory pain and neuropathic pain. The first, inflammation associated, is caused by tissue damage (Fig. 1A,B). The first lesion and the inflammatory process cause Ad and C fibers alteration. These fibers are responsible of sensi-tization, recruitment of nociceptors normally silent and ionic channels and membrane receptors activation. Neurogenic pain syndromes arise as consequence of central and peripheral nerve damage. During inflammation and neuropathies there are phenotypic changes of the dorsal root ganglions (DRGs) with an increase in excitability, immune system signal alteration in the CNS, endocrine modifications. It has been demonstrated that after damage nociceptors become hyperexcitable. IMMUNE CELL INVOLVMENT IN NEUROPATHIC PAIN The activation of the immune system has a main role in both peripheral and central abnormal sensory processing. Zuo et al. (2003) indicated that mast cells were activated in a model of partial sciatic nerve injury. Perkins and Tracey (2000) studied and showed an invasion of endoneural neutrophils into the damaged nerve—a process that peaked 24 h after injury. Neuro-pathic pain symptoms did not develop after depleting circulating neutrophilis at the time of nerve injury but established symptoms did not reverse (Perkins and Tracey, 2000). Therefore, neutrophils could have an important role in the early stage if neuropathic could have an important role in the early stage of neuropathic pain development. Several lines of evidence indicate that macrophages and the development of allodynia or hyperalgesia (Heumann, 1987; Myers et al., 1996; Sommer and Schafers, 1998; Cui et al., 2000; Liu et al., 2000). A temporal correlation between the invasion of blood-born, macrophages and the development of allodynia or hyperalgesia was shown. Furthermore, a lack of thermal hyperalgesia in a neuropathic model in the WDl mouse, which shows delayed recruitment for non-resident macrophages, has been reported. Rutkowski et al. (2002) failed to relieve mechanical allodynia after clodronate administration. Along with or after macrophage recruitment, T cells are infiltrated into damage nerves, but their involve-ment in neuropathic pain has been poorly studied. Few studies have focused on the infiltration of immune cells into the spinal cord after peripheral nerve injury, in particular hematogenous leukocytes and resident microglia (Sweitzer et al., 2002). Fluorocitrate treatment, which blocks astrocyte and microglia metabolism, inhibits neuropathic pain, whereas minocycline, specific microglial inhibitor, blocks the development of neuropathic pain states but does not reduce pain that is already established (Raghavendra et al., 2003). The spinal implantation of microglia, activated in vitro, simulated signs of neuropathic pain (mechan-ical allodynia). Microglial activation, as new studies reveal (Zhuang et al., 2005), seems to be the first step in the activation of immune responses in CNS. In fact, microglia might be responsible for the initiation of neuropathic pain states, and astrocytes may be involved in their maintenance (Tanga et al., 2005; Zhuang et al., 2005).
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