Abnormal Reinnervation of Denervated Areas Following Nerve Injury Facilitates Neuropathic Pain

Abstract

An injury to peripheral nerves leads to skin denervation, which often is followed by increased pain sensitivity of the denervated areas and the development of neuropathic pain. Changes in innervation patterns during the reinnervation process of the denervated skin could contribute to the development of neuropathic pain. Here, we examined the changes in the innervation pattern during reinnervation and correlated them with the symptoms of neuropathic pain. Using a multispectral labeling technique—PainBow, which we developed, we characterized dorsal root ganglion (DRG) neurons innervating distinct areas of the rats’ paw. We then used spared nerve injury, causing partial denervation of the paw, and examined the changes in innervation patterns of the denervated areas during the development of allodynia and hyperalgesia. We found that, differently from normal conditions, during the development of neuropathic pain, these areas were mainly innervated by large, non-nociceptive neurons. Moreover, we found that the development of neuropathic pain is correlated with an overall decrease in the number of DRG neurons innervating these areas. Importantly, treatment with ouabain facilitated reinnervation and alleviated neuropathic pain. Our results suggest that local changes in peripheral innervation following denervation contribute to neuropathic pain development. The reversal of these changes decreases neuropathic pain.

The input-output relation of primary nociceptive neurons is determined by the morphology of the peripheral nociceptive terminals

“…It was recently demonstrated that neuropathic pain following nerve injury was associated with a decreased number of DRG neuronal somata innervating the hypersensitive area (Leibovich et al, 2020) and increased number of axons innervating the area (Duraku et al, 2012). Together these results suggest that each DRG neuron innervating the hypersensitive area increases the complexity of its terminal fibers.…”

The Input-Output Relation of Primary Nociceptive Neurons is Determined by the Morphology of the Peripheral Nociceptive Terminals

“…An increase in the number of terminal branches to 16, simulating hyperinnervation changes (Cain et al, 2001;Leibovich et al, 2020) leads to an increase in firing (Figure 12A, red). A decrease in the number of the terminal branches to 7, simulating a denervation state, substantially decreases the nociceptive gain (Figure 12A, blue).…”

“…Together these results suggest that each DRG neuron innervating the hypersensitive area increases the complexity of its terminal fibers. Our model predicts that the increase in the terminal branching of individual DRG neurons following nerve injury (Leibovich et al, 2020) or inflammation or tumor formation (Cain et al, 2001) affects neuronal excitability and thus may contribute to the development of pain hypersensitivity in neuropathic conditions.…”

“…Thus, noxious stimuli activate morphologically complex excitable structures, which differ among primary nociceptive neurons. Importantly, the morphology of terminal trees changes with age or under pathological conditions (Cain et al, 2001;Chartier et al, 2018;Lakatos et al, 2020;Leibovich et al, 2020).…”

Novel Insights into Molecular Mechanisms of Chronic Pain

“…In a further approach, they enhanced the sprouting of nerves by the drug oubain and observed that this treatment drastically reduced the neuropathic pain behavior. From these results, it can be concluded that dysfunctional reinnervation of injured areas is involved in the development of neuropathic pain and that pharmacological support of reinnervation, e.g., by oubain, might exert a useful approach for the treatment of nerve injury-induced pain [ 13 ]. David Romeo-Guitart and Caty Casas described a new approach to modulate axonal regeneration and neuropathic pain at the same time by the use of a drug combination called NeuroHeal which has been identified using machine learning [ 14 ].…”