Gracile Neurons Contribute to the Maintenance of Neuropathic Pain in Peripheral and Central Neuropathic Models

Abstract

In the present study, we compared the roles of gracile neurons in mechanically-induced neuropathic pain caused by spinal injury and L5 spinal nerve ligation in rats. Behavioral and electrophysiological methods were used to measure mechanical allodynia in the hindpaws, and excitability of the gracile neurons in the medulla, respectively. In the spinal hemisection and spinal contusion models, mechanical allodynia developed in both hindpaws and lasted over a month. Three weeks following the hemisection, gracile neurons identified as wide-dynamic-range (WDR) and low-threshold (LT) neurons, showed increased neuronal activity to non-noxious mechanical stimuli compared to control groups, whereas the spinal contusion groups did not show evoked activity (*p<0.05). A lesion of the gracile nucleus partially reversed the existing mechanical allodynia in both hindpaws compared to prior to the injury in the hemisection group, whereas the spinal contusion groups did not show significant changes (*p<0.05). In the spinal nerve ligation model, mechanical allodynia developed at the ipsilateral (injured) side of the hindpaw. In addition, WDR neuronal activity at the ipsilateral gracile neurons showed a significant increase with non-noxious mechanical stimuli, whereas the LT neurons did not show significant changes (*p<0.05). Similarly to the hemisection model, a lesion of the gracile nucleus attenuated the mechanical allodynia in spinal nerve ligation models. The present data suggest that gracile neurons contribute to the maintenance of non-noxious mechanically-induced neuropathic pain in both hemisection- and ligation-induced neuropathic pain in rats.

A critical time window for the analgesic effect of central histamine in the partial sciatic ligation model of neuropathic pain

“…These results may imply that pathophysiological changes in the spinal level following partial sciatic nerve injury are more associated with thermal hyperalgesia, while those in supraspinal level are associated with mechanical allodynia in addition to thermal hyperalgesia. This speculation is partially supported by the previous studies reporting that ascending input to nucleus gracilis is critical to the manifestation of tactile allodynia [ 43 – 45 ]. Therefore, it is possible that histamine may inhibit both mechanical allodynia and thermal hyperalgesia of CRPS-2 through acting on H 1 receptors at the supraspinal levels.…”

Reappraising neuropathic pain in humans—how symptoms help disclose mechanisms

“…[127][128][129] Sensitization of ascending pain systems rapidly progresses caudo-rostrally, and anatomical and functional changes proceed from dorsal horn to brainstem to thalamus and cortex. 130 Spinal, thala mic and cortical lesions that cause allodynia induce multilevel, trans-synaptic astrocyte and microglial activation, 131,132 secretion of nociceptive neurotansmitters by non-nociceptive afferents, 133 and a decrease in thalamic GABAergic inhibition. 134 Deafferentation of sensory thala mic neurons due to lesions in ascending somatosensory systems is associated with metabolic depression in the thalamus, as demonstrated in human recordings by repetitive, low-threshold calcium spike bursting.…”

The Dorsal Column Nuclei Scale Mechanical Sensitivity in Naive and Neuropathic Pain States

“…Blockade of DCN activity via pharmacology or lesion ameliorates tactile hypersensitivity during neuropathic pain 21,106 . This work suggests that DCN activity contributes to tactile hypersensitivity during neuropathic pain.…”

“…Interestingly, activity in the DCN is altered during chronic pain. DCN neurons exhibit more spontaneous activity and afterdischarge during both inflammatory 20 and neuropathic pain 21,22 conditions, and display increased recruitment to peripheral nerve stimulation following nerve injury 23,24 . Furthermore, spinal changes associated with neuronal hyperactivity during injury-induced neuropathic pain, such as microglial recruitment 25 and upregulation of neuropeptides 26,27 , are mirrored in the DCN 28,29 .…”