Abstract
The pain experience depends on the relay of nociceptive signals from the spinal cord dorsal horn to higher brain centers. This function is ultimately achieved by the output of a small population of highly specialized neurons called projection neurons (PNs). Like output neurons in other central nervous system (CNS) regions, PNs are invested with a substantial axon collateral system that ramifies extensively within local circuits. These axon collaterals are widely distributed within and between spinal cord segments. Anatomical data on PN axon collaterals have existed since the time of Cajal, however, their function in spinal pain signaling remains unclear and is absent from current models of spinal pain processing. Despite these omissions, some insight on the potential role of PN axon collaterals can be drawn from axon collateral systems of principal or output neurons in other CNS regions, such as the hippocampus, amygdala, olfactory cortex, and ventral horn of the spinal cord. The connectivity and actions of axon collaterals in these systems have been well-defined and used to confirm crucial roles in memory, fear, olfaction, and movement control, respectively. We review this information here and propose a framework for characterizing PN axon collateral function in the dorsal horn. We highlight that experimental approaches traditionally used to delineate axon collateral function in other CNS regions are not easily applied to PNs because of their scarcity relative to spinal interneurons (INs), and the lack of cellular organization in the dorsal horn. Finally, we emphasize how the rapid development of techniques such as viral expression of optogenetic or chemogenetic probes can overcome these challenges and allow characterization of PN axon collateral function. Obtaining detailed information of this type is a necessary first step for incorporation of PN collateral system function into models of spinal sensory processing.
Highlights
Specialty section: This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology
As for other sensory modalities, such as touch, heat/cold, and itch, we have a good understanding of the anatomy of the pathway over which noxious signals generated in skin, muscle, joints, and viscera travels to the brain via a series of synaptic connections on neurons located in various central nervous system (CNS) regions or “pain nodes.”
This review focuses on what we believe is an overlooked element in dorsal horn pain processing, namely the role of projection neurons (PNs) axon collaterals that branch and terminate locally
Summary
While it is widely appreciated that acute pain serves important biological functions, persistent or ongoing pain serves no apparent biological purpose, but has far-reaching impacts on patients and society. As for other sensory modalities, such as touch, heat/cold, and itch, we have a good understanding of the anatomy of the pathway over which noxious (or potentially painful) signals generated in skin, muscle, joints, and viscera travels to the brain via a series of synaptic connections on neurons located in various CNS regions or “pain nodes.”. Textbook accounts have the axons of PNs terminating in the thalamus before being relayed to somatosensory cortex and limbic structures where the pain percept and its emotional or effective responses are generated While this holds true for primates, recent work in rodents, has provided evidence for extensive PN axon terminals in brain stem centers, such as the nucleus of the solitary tract, caudal ventrolateral medulla, parabrachial nucleus (PBN), and the periaqueductal gray (Al-Khater and Todd, 2009; Cameron et al, 2015)
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