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Many pathological processes within the central nervous system are mediated by complex interactions between neurons and resident glial cells. In the case of painful peripheral neuropathy, spinal microglia react and undergo a series of changes that directly influence the establishment of neuropathic pain states. Purinergic signaling has been shown to be at the center of this reactivity, and here we review recent mechanistic advances describing the importance of microglial P2 receptors and their interactions with neuronal populations in the development of neuropathic pain.

Peripheral neuropathic pain is the most debilitating of all clinical pain syndromes and affects a large and growing number of people worldwide. There are diverse causes for peripheral neuropathic pain, which may be experienced after traumatic nerve injury or from diseases that affect peripheral nerves, such as diabetes, HIV/AIDS, and cancer, and it can also result from toxic chemicals, such as cancer chemotherapy agents. Despite these varying causes, it is clear that neuropathic pain is due to persistent pathological alterations resulting in hyperexcitability in the peripheral and central nervous systems, and it is the neuropathology that must be targeted for effective therapy of which there is none presently available. Mechanistically, neuropathic pain is distinct from acute pain and inflammatory pain, for which many effective therapies are known. In this review, we describe the relationships between clinical symptoms and experimental models of peripheral neuropathic pain, and we provide a framework for understanding the potential mechanisms that involve primary neuronal dysfunction as well as pathological changes in neuron-glial signaling. Drug Dev. Res. 67:289–301, 2006. © 2006 Wiley-Liss, Inc.

The dorsal horn of the spinal cord in the newborn rat is characterized by large cutaneous mechanoreceptive fields, a predominance of A-fibre synaptic inputs and diffuse primary afferent A-fibre projections, all of which are gradually reduced and refined over the first postnatal weeks. This may be partly responsible for the reduction in cutaneous flexion reflex sensitivity of rats over the postnatal period. Here we show that chronic, local exposure of the dorsal horn of the lumbar spinal cord to the NMDA antagonist MK801 from birth prevents the normal functional and structural reorganization of A-fibre connections. Dorsal horn cells in spinal MK801-treated animals, investigated at eight weeks of age by in vivo electrophysiological recording, had significantly larger cutaneous mechanoreceptive fields and greater A-fibre evoked responses than vehicle controls. C-fibre evoked responses were unaffected. Chronic MK801 also prevented the normal structural reorganization of A-fibre terminals in the spinal cord. The postnatal withdrawal of superficially projecting A-fibre primary afferents to deeper laminae did not occur in treated animals although C-fibre afferent terminals and cell density in the dorsal horn were apparently unaffected. Spinal MK801-treated animals also had significantly reduced behavioural reflex thresholds to mechanical stimulation of the hindpaw compared to naive and vehicle-treated animals, whereas noxious heat thresholds remained unaffected. The results indicate that the normal postnatal structural and functional development of A-fibre sensory connectivity within the spinal cord is an activity-dependent process requiring NMDA receptor activation.

Neurons in the superficial laminae of the dorsal horn are dominated by input from peripheral nociceptors. Following peripheral nerve injury, low threshold mechanoreceptive Aβ-fibers sprout from their normal termination site in laminae III/IV into laminae I–II and this structural reorganization may contribute to neuropathic tactile pain hypersensitivity. We have now investigated whether a sciatic nerve crush injury alters the behavioral response in rats to tactile stimuli and whether this is associated with a change in the pattern of c-Fos expression in the dorsal horn and the parabrachial area of the brainstem. Sciatic nerve crush resulted in a patchy but marked tactile allodynia manifesting first at 3 weeks and persisting for up to 52 weeks. C-Fos expression in the dorsal horn and parabrachial region was never observed on brushing the skin of the sciatic nerve territory in animals with intact nerves, but was found after sciatic nerve crush with peripheral regeneration. We conclude that after nerve injury, low threshold mechanoreceptor fibers may play a major role in producing pain-related behavior by activating normally nociceptive-specific regions of the central nervous system such as the superficial laminae of the dorsal horn and the parabrachial area. J. Comp. Neurol. 428:45–61, 2000. © 2000 Wiley-Liss, Inc.