Cellular signalling pathways of spinal pain neuroplasticity as targets for analgesic development

Nociceptive inputs from primary afferents are primarily mediated at fast glutamatergic synapses onto second order neurons in the dorsal horn of the spinal cord through activation of AMPA/kainate and NMDA receptor subtypes of ionotropic glutamate receptors. At these glutamatergic synapses several forms of short-lasting and long-lasting enhancement of synaptic transmission are known. Enhancement of excitatory synaptic transmission in nociceptive pathways is thought to be a key neural substrate underlying chronic pain, and thus the cellular and molecular mechanisms producing this enhancement represent potential targets for developing novel forms of therapeutics. Central to the mechanisms for pain hypersensitivity is the NMDA receptor, the activity of which is facilitated by convergent intracellular biochemical cascades in dorsal horn neurons. Cellular changes are not restricted to neurons in the dorsal horn, however, and there is growing evidence for involvement of glia, and of glia-neuronal signaling, in initiating and sustaining enhancement of nociceptive transmission. In particular, a role has emerged for microglia in pain hypersensitivity following nerve injury. This expanded understanding of cellular and molecular signalling mechanisms in the dorsal horn, that includes both neurons and glia, provides a basis of creating new types of strategies for management, and also for diagnosis, of chronic pain.