Elsevier

Neuroscience

Volume 140, Issue 4, 2006, Pages 1311-1320
Neuroscience

Pain mechanism
Descending facilitation from the rostral ventromedial medulla maintains nerve injury-induced central sensitization

https://doi.org/10.1016/j.neuroscience.2006.03.016Get rights and content

Abstract

Nerve injury can produce hypersensitivity to noxious and normally innocuous stimulation. Injury-induced central (i.e. spinal) sensitization is thought to arise from enhanced afferent input to the spinal cord and to be critical for expression of behavioral hypersensitivity. Descending facilitatory influences from the rostral ventromedial medulla have been suggested to also be critical for the maintenance, though not the initiation, of experimental neuropathic pain. The possibility that descending facilitation from the rostral ventromedial medulla is required for the maintenance of central sensitization was examined by determining whether ablation of mu-opioid receptor-expressing cells within the rostral ventromedial medulla prevented the enhanced expression of repetitive touch-evoked FOS within the spinal cord of animals with spinal nerve ligation injury as well as nerve injury-induced behavioral hypersensitivity. Rats received a single microinjection of vehicle, saporin, dermorphin or dermorphin–saporin into the rostral ventromedial medulla and 28 days later, underwent either sham or spinal nerve ligation procedures. Animals receiving rostral ventromedial medulla pretreatment with vehicle, dermorphin or saporin that were subjected to spinal nerve ligation demonstrated both thermal and tactile hypersensitivity, and showed significantly increased expression of touch-evoked FOS in the dorsal horn ipsilateral to nerve injury compared with sham-operated controls at days 3, 5 or 10 post-spinal nerve ligation. In contrast, nerve-injured animals pretreated with dermorphin–saporin showed enhanced behaviors and touch-evoked FOS expression in the spinal dorsal horn at day 3, but not days 5 and 10, post-spinal nerve ligation when compared with sham-operated controls. These results indicate the presence of nerve injury-induced behavioral hypersensitivity associated with nerve injury-induced central sensitization. Further, the results demonstrate the novel concept that once initiated, maintenance of nerve injury-induced central sensitization in the spinal dorsal horn requires descending pain facilitation mechanisms arising from the rostral ventromedial medulla.

Section snippets

Experimental procedures

Male, Sprague–Dawley rats (Harlan, Indianapolis, IN, USA), weighing 200–300 g at the time of surgery were maintained in a climate-controlled room on a 12-h light/dark cycle (light on at 07:00 h). Food and water were available ad libitum. All testing and surgeries were performed in accordance with the policies and recommendations of the International Association for the Study of Pain and the National Institutes of Health guidelines for the handling and use of laboratory animals. These studies

Microinjection sites

Histological verification at the end of the experiments demonstrated the injection sites and cannula tracks as shown in Fig. 1. These microinjection sites have previously been shown to reduce the mRNA signal for the mu opioid receptor in the RVM and surrounding areas including the nucleus gigantocellularis (NGC) (Porreca et al., 2001).

Dermorphin–saporin microinjection and behavioral hypersensitivity

Rats (n=8 per group) received a single bilateral microinjection of distilled water (0.5 μl), dermorphin (3 pmol), saporin (3 pmol), or dermorphin–saporin

Discussion

In the present study, repetitive non-noxious tactile stimulation of the hindpaw produced an increase in the number of FOS-positive cells in the ipsilateral spinal dorsal horn of animals that had received SNL when compared with FOS expression in animals that received sham surgery. The increase in FOS-positive cells was seen in both the superficial and deep dorsal horn laminae and correlated in time with the expression of nerve injury-induced mechanical and thermal hypersensitivity, behaviors

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