Loss of Neurons from Laminas I-III of the Spinal Dorsal Horn Is Not Required for Development of Tactile Allodynia in the Spared Nerve Injury Model of Neuropathic Pain

Abstract

It has been proposed that death of inhibitory interneurons in the dorsal horn contributes to the neuropathic pain that follows partial nerve injury. In this study, we have used two approaches to test whether there is neuronal death in the dorsal horn in the spared nerve injury (SNI) model. We performed a stereological analysis of the packing density of neurons in laminas I-III 4 weeks after operation and found no reduction on the ipsilateral side compared with that seen on the contralateral side or in sham-operated or naive rats. In addition, we used two markers of apoptosis, terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) staining and immunocytochemical detection of cleaved (activated) caspase-3. Neither of these methods demonstrated apoptotic neurons in the dorsal spinal cord 1 week after operation. Although TUNEL-positive cells were present throughout the gray and white matter at this stage, they were virtually all labeled with antibody against ionized calcium-binding adapter molecule 1, a marker for microglia. All animals that underwent SNI showed clear signs of tactile allodynia affecting the ipsilateral hindpaw. These results suggest that a significant loss of neurons from the dorsal horn is not necessary for the development of tactile allodynia in the SNI model.

Intrathecal midazolam regulates spinal AMPA receptor expression and function after nerve injury in rats

“…While the endogenous GABAergic activity may play a role in the regulation of spinal nociceptive processing, it is possible that this function could be diminished after nerve injury presumably due to a potential loss of spinal GABAergic interneurons (Sugimoto et al, 1990;Mao et al, 1997;Scholz et al, 2005). These findings add to the discussion concerning the role of spinal GABAergic neurons in the mechanisms of neuropathic pain (Polgar et al, 2005;Scholz et al, 2005). It seems reasonable to suggest that preserving endogenous spinal GABAergic activity alone after nerve injury might be insufficient to counter-balance spinal excitation induced by glutamatergic activities, as indicated by our data showing that AMPA receptor-mediated spinal excitation induced nociceptive responses in naïve rats even in the presence of an intact endogenous GABAergic system (i.e., without nerve injury).…”

“…Spinal glutamatergic and γ-aminobutyric acid (GABA)ergic systems are among several proposed mechanisms of neuropathic pain and have been extensively investigated over the last two decades (Dubner, 1991;Dougherty and Willis, 1991;Yamamoto and Yaksh, 1992;Mao et al, 1995;Woolf and Mannion, 1999;Hammond 2001). Evidence exists indicating that either activation of the glutamatergic system or a possible loss of GABAergic activity, or both, after peripheral nerve injury contributes to the development and maintenance of neuropathic pain behaviors in rats (Mao et al, 1995;Bridges et al, 2001;Cronin et al, 2004;Polgar et al, 2005;Scholz et al, 2005). These earlier studies suggest a possible interaction between these regulatory systems within the central nervous system.…”

A Critical Role of Toll-like Receptor 2 in Nerve Injury-induced Spinal Cord Glial Cell Activation and Pain Hypersensitivity

“…Thus far, the involvement of neuronal cell death in neuropathic pain is controversial. Although it has been reported that DRG neuronal cells undergo cell death upon peripheral nerve damage (51)(52)(53), others failed to detect neuronal cell death (54). In another study, it was suggested that inhibitory interneurons in the spinal dorsal horn die upon peripheral nerve injury (55,56).…”

Sodium Channel Nav1.7 Is Essential for Lowering Heat Pain Threshold after Burn Injury

“…We compared reactive microglial Iba-1 staining (Polgár et al, 2005;Narita et al, 2006) in sham-treated versus burn model animals at several time points. As a positive control, we stained lumbar spinal cord from mice that had undergone sciatic axotomy 1 week before.…”