Molecular Anatomy of Synaptic and Extrasynaptic Neurotransmission Between Nociceptive Primary Afferents and Spinal Dorsal Horn Neurons.

Sensory signals generated by peripheral nociceptors are transmitted by peptidergic and nonpeptidergic nociceptive primary afferents to the superficial spinal dorsal horn, where their central axon terminals establish synaptic contacts with secondary sensory spinal neurons. In the case of suprathreshold activation, the axon terminals release glutamate into the synaptic cleft and stimulate postsynaptic spinal neurons by activating glutamate receptors located on the postsynaptic membrane. When overexcitation is evoked by peripheral inflammation, neuropathy or pruritogens, peptidergic nociceptive axon terminals may corelease various neuropeptides, neurotrophins and endomorphin, together with glutamate. However, in contrast to glutamate, neuropeptides, neurotrophins and endomorphin are released extrasynaptically. They diffuse from the site of release and modulate the function of spinal neurons via volume transmission, activating specific extrasynaptic receptors. Thus, the released neuropeptides, neurotrophins and endomorphin may evoke excitation, disinhibition or inhibition in various spinal neuronal populations, and together with glutamate, induce overall overexcitation, called central sensitization. In addition, the synaptic and extrasynaptic release of neurotransmitters is subjected to strong retrograde control mediated by various retrogradely acting transmitters, messengers, and their presynaptic receptors. Moreover, the composition of this complex chemical apparatus is heavily dependent on the actual patterns of nociceptive primary afferent activation in the periphery. This review provides an overview of the complexity of this signaling apparatus, how nociceptive primary afferents can activate secondary sensory spinal neurons via synaptic and volume transmission in the superficial spinal dorsal horn, and how these events can be controlled by presynaptic mechanisms.