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  • There are profound differences between

    2024-04-10

    There are profound differences between acute and chronic pain when dramatic changes occur in peripheral nociceptors and central nociceptive pathways and the pain system is sensitised thereby leading to exaggerated responses to noxious stimuli (hyperalgesia) and responses to non-noxious stimuli (allodynia) (Sandkühler, 2009). Tissue injury results in inflammatory pain in diseases such as rheumatoid arthritis (Üçeyler et al., 2009). Neuropathic pain results from lesions to the peripheral nervous system caused by mechanical trauma, metabolic diseases such as diabetes or neurotoxic chemicals such as chemotherapeutic agents. In chronic pain states the increased nociceptive input from the periphery triggers the physiological plasticity and long lasting transcriptional and post-translational changes in the CNS defined as central sensitization (Kuner, 2010). Glial Tubastatin A in the spinal cord, such as microglia and astrocytes, also contribute to central sensitization (Malcangio, 2016, McMahon and Malcangio, 2009) and cortical and sub-cortical structures modulate pain (Eippert et al., 2009). Under neuropathic pain conditions, loss of function of inhibitory neurons at the level of the spinal cord contributes to the increased excitation and in chronic inflammatory pain GABAergic inhibition is decreased in the spinal cord (Takazawa et al., 2017, Zeilhofer et al., 2012).
    GABA is expressed by inhibitory interneurons in the laminae I-III of the dorsal horns which constitute a different neuronal population from excitatory interneurons expressing glutamate (Polgar et al., 2003, Polgár et al., 2013, Zeilhofer et al., 2012). GABAergic islet cells that contain parvalbumin are innervated by myelinated primary afferent fibres which receive axoaxonic synapses from GABAergic cells. Such GABA-mediated pre-synaptic inhibition is likely to regulate myelinated fibres activity following non-noxious mechanical stimulation in the periphery. GABAergic interneurons which also contain neuropeptide Y innervate projection neurons expressing NK1 receptor for Substance P (SP) and those which also contain nNOS innervate giant cells in lamina I. As NK1 projection neurons are innervated by the nociceptive C fibres, these GABAergic synapses are likely to regulate activity in response to nociceptive inputs from the periphery. GABA modulates nociceptive transmission at the level of the dorsal horn through activation of both GABAA and GABAB receptors that are located on primary afferent terminals as well as dorsal horn neurones, including lamina I spinothalamic projection neurons (Calver et al., 2000). In the spinal cord GABAB receptors regulate the activity of both peptidergic primary afferent terminals and dorsal horn neurons. Indeed, baclofen application to the dorsal horns isolated in vitro inhibits the release of SP evoked by activation of primary afferent fibres (Malcangio Tubastatin A and Bowery, 1993) as well as the internalization of the NK1 receptors on projection neurons (Marvizon et al., 1999). Baclofen inhibits C fibre-evoked activity of convergent/multireceptive neurons in anaesthetised rats (Dickenson et al., 1985). Furthermore, baclofen inhibits c-fos expression in dorsal horn neurons after exogenous SP application (Riley et al., 2001). Notably, the effect of baclofen on NK1 receptor internalization are significant after intrathecal rather than systemic administration which results, as discussed above, in a predominant muscle relaxant effect (Riley et al., 2001). GABAB receptors are localized on the terminals of peptidergic primary afferents fibers (Malcangio et al., 1993, Price et al., 1984). At presynaptic sites the GABAB receptor activation leads to inhibition of high voltage-gated Ca2+ channel activity and inhibits glutamate as well as SP and CGRP release (Bowery, 2006, Malcangio and Bowery, 1993, Malcangio and Bowery, 1995, Marvizon et al., 1999). The decrease of dorsal horn neuron excitability (Kangrga et al., 1991), and the regulation of intrinsic neuronal properties (Derjean et al., 2003) suggest an additional postsynaptic site for the baclofen action on pain.