P3Neural circuits for pain modulation in the central nervous system

Abstract

Pain is a common and severe disease that affects millions of people worldwide and is difficult to treat. The main reason is that the mechanisms for pain information transmission and modulation have still not revealed. In the central nervous system (CNS), there are many long and short neural circuits constituted by axonal processes and are necessary for pain sensation. But the structures and functions of these pathways, especially those constituted by local axons and their collaterals are not known, which is essential for us to uncover the neural mechanisms of pain [1]. In our recent studies, the neural circuits involved in pain sensation in the CNS have been investigated with different methods, especially under the electron microscopic level [2]. The main results are as follows: (1) In the superficial laminae (lamina I and lamina II) of the spinal dorsal horn (SDH), substance P-immunoreactive (SP-ir) and calcitonin gene-related peptide (CGRP)-ir primary afferent terminals have been observed to make synapses with GABA- and glycine-ir neurons which could be activated by periphery painful stimulation, suggesting that the noxious information might be regulated by inhibitory interneurons in the SDH. (2) Endomorphin (EM) is a new member of the endogenous opioid family and specific ligand for μ-opioid receptor (MOR) [3]. Within the superficial laminae of the SDH, either EM-ir fibers from the primary afferents (Figure 1) or serotonin (5-HT)-ir fibers from the descending fibers of the brainstem raphe nuclei have been encountered to terminate onto the same neurons which send projection fibers to the parabrachial nucleus (PBN) or ventrolateral complex of the thalamus, indicating that the SDH might be a very special site for pain modulation. (3) Neurons in layer V of the anterior cingulate cortex (ACC) innervated by direct ascending fibers from the spinal dorsal horn, and then in turn, projected directly to the SDH. The excitation of these ACC-SDH projection neurons by nociceptive inputs could facilitate the activity of the nociceptive neurons in lamina I of the SDH, suggesting that the descending projection from ACC to SDH might directly potentiate the noxious information transmission. This effect might affect the patient and make them to feel much more painful [4]. (4) In the periaqueductal gray, EM released from the terminals originated from the EM-containing neurons in the hypothalamus binds to MOR expressing GABAeregic inhibitory interneurons and then results in disinhibition of 5-HTergic projection neurons, and finally to exert analgesic effects at the spinal cord level [5]. These results have provided morphological and functional evidence for the mechanisms underlying pain information transmission and modulation in the CNS.