Neuron-Glia-Immune Triad and Cortico-Limbic System in Pathology of Pain

Abstract

Pain is an unpleasant sensation that alerts one to the presence of obnoxious stimuli or sensations. These stimuli are transferred by sensory neurons to the dorsal root ganglia-spinal cord and finally to the brain. Glial cells in the peripheral nervous system, astrocytes in the brain, dorsal root ganglia, and immune cells all contribute to the development, maintenance, and resolution of pain. Both innate and adaptive immune responses modulate pain perception and behavior. Neutrophils, microglial, and T cell activation, essential components of the innate and adaptive immune responses, can play both excitatory and inhibitory roles and are involved in the transition from acute to chronic pain. Immune responses may also exacerbate pain perception by modulating the function of the cortical-limbic brain regions involved in behavioral and emotional responses. The link between an emotional state and pain perception is larger than what is widely acknowledged. In positive psychological states, perception of pain along with other somatic symptoms decreases, whereas in negative psychological states, these symptoms may worsen. Sex differences in mechanisms of pain perception are not well studied. In this review, we highlight what is known, controversies, and the gaps in this field.

Keywords: central nervous system; dorsal root ganglia; gliopathic pain; mental health; pain perception.

Figure 1

Pain pathways and levels of regulation. (A) The pain signal cascades through the central and peripheral nervous systems. Noxious sensory inputs from the lower and upper parts of the body are sensed by the afferent neurons that feed to the lumbar and the cervical spinal cord divisions, respectively. The information is relayed to the primary somatosensory cortex of the cerebrum; interneurons in the CNS transmit information to the efferent neurons that relay signals from the CNS to the effector organs, such as the muscles and glands. (B) The neurons in the CNS or the PNS are surrounded by glial cells. Resident or infiltrated immune cells release mediators that in turn modulate glial and neurons activity function at various levels. (C) Pain signal is regulated at several levels; an individual’s cognitive state regulates pain perception. The limbic system is key for integrating pain perception. Immune and glial cells respond to injury or noxious stimuli and modulate function of dorsal root ganglia, trigeminal ganglion, and limbic structures to alter pain perception. All these inputs are integrated and together constitute one’s cognitive state, which can affect pain perception and experience. Pain can be regulated at each level via the mediators summarized in Table 1.