An Index Combining Lost and Remaining Nerve Fibers Correlates with Pain Hypersensitivity in Mice

Abstract

Multiple peripheral nerves are known to degenerate after nerve compression injury but the correlation between the extent of nerve alteration and pain severity remains unclear. Here, we used intravital two-photon fluorescence microscopy to longitudinally observe changes in cutaneous fibers in the hind paw of Nav1.8-Cre-tdTomato mice after chronic constriction injury (CCI). Results showed that the CCI led to variable loss of the skin nerve plexus and intraepidermal nerve fibers. The timing of Nav1.8 nerve fiber loss correlated with the development of mechanical hypersensitivity. We compared a scoring approach that assessed whole-paw nerve degeneration with an index that quantified changes in the nerve plexus and terminals in multiple small regions of interest (ROI) from intravital images of the third and fifth toe tips. We found that the number of surviving nerve fibers was not linearly correlated with mechanical hypersensitivity. On the contrary, at 14 days after CCI, the moderately injured mice showed greater mechanical hypersensitivity than the mildly or severely injured mice. This indicates that both surviving and injured nerves are required for evoked neuropathic pain. In addition, these two methods may have the estimative effect as diagnostic and prognostic biomarkers for the assessment of neuropathic pain.

An improved conflict avoidance assay reveals modality-specific differences in pain hypersensitivity across sexes

“…For instance, mechanical hypersensitivity is greater with a moderate loss of sensory afferents, and thermal hypersensitivity develops as uninjured nociceptors invade denervated territories. 11 , 19 Finally, the onset of mechanical allodynia, unlike thermal hyperalgesia, is often associated with central sensitization mechanisms involving spinal neurons. 21 , 74 , 79 …”

“…For instance, mechanical hypersensitivity is greater with a moderate loss of sensory afferents, and thermal hypersensitivity develops as uninjured nociceptors invade denervated territories. 11,19 Finally, the onset of mechanical allodynia, unlike thermal hyperalgesia, is often associated with central sensitization mechanisms involving spinal neurons. 21,74,79 Female mice developed significant aversion to mechanical stimuli with lesser heat aversion, which confirms that mechanical hypersensitivity shares a common mechanism in both sexes, probably relying on spinal cord disinhibition.…”

Transient immune activation without loss of intraepidermal innervation and associated Schwann cells in patients with complex regional pain syndrome

“…CCI and sham mice served as models but had comparable IENFD. The regional differences in innervation in plantar mouse skin, high variability, or a short injury duration might have obscured a loss in IENFD [ 39 ]. Most importantly, we could detect many intraepidermal Schwann cell processes and their density correlated strongly with the IENFD, matching with the data and the reported interdependence of nociceptive Schwann cells and IENFs [ 22 ].…”