Nerve injury proximal or distal to the DRG induces similar spinal glial activation and selective cytokine expression but differential behavioral responses to pharmacologic treatment

Abstract

The specific mechanisms by which nervous system injury becomes a chronic pain state remain undetermined. Historically, it has been believed that injuries proximal or distal to the dorsal root ganglion (DRG) produce distinct pathologies that manifest in different severity of symptoms. This study investigated the role of injury site relative to the DRG in (1) eliciting behavioral responses, (2) inducing spinal neuroimmune activation, and (3) responding to pharmacologic interventions. Rats received either an L5 spinal nerve transection distal to the DRG or an L5 nerve root injury proximal to the DRG. Comparative studies assessed behavioral nociceptive responses, spinal cytokine mRNA and protein expression, and glial activation after injury. In separate studies, intrathecal pharmacologic interventions by using selective cytokine antagonists (interleukin-1 [IL-1] receptor antagonist and soluble tumor necrosis factor [TNF] receptor) and a global immunosuppressant (leflunomide) were performed to determine their relative effectiveness in these injury paradigms. Behavioral responses assessed by mechanical allodynia and thermal hyperalgesia were almost identical in the two models of persistent pain, suggesting that behavioral testing may not be a sensitive measure of injury. Spinal IL-1beta, IL-6, IL-10, and TNF mRNA and IL-6 protein were significantly elevated in both injuries. The overall magnitude of expression and temporal patterns were similar in both models of injury. The degree of microglial and astrocytic activation in the L5 spinal cord was also similar for both injuries. In contrast, the pharmacologic treatments were more effective in alleviating mechanical allodynia for peripheral nerve injury than nerve root injury, suggesting that nerve root injury elicits a more robust, centrally mediated response than peripheral nerve injury. Overall, these data implicate alternate nociceptive mechanisms in these anatomically different injuries that are not distinguished by behavioral testing or the neuroimmune markers used in this study.

Spinal Glia and Proinflammatory Cytokines Mediate Mirror-Image Neuropathic Pain in Rats

“…Experiment 1: effect of intrathecal fluorocitrate on sciatic inflammatory neuropathy-induced allodynia: blockade of allodynia Immunohistochemical evidence of bilateral astrocyte and microglial activation has been observed after traumatic neuropathies (Colburn et al, 1999;Winkelstein et al, 2001). Whether glial activation is the consequence of nerve trauma or nerve inflammation in these models is unknown.…”

“…Notably, the resultant exaggerated pain state is mediated by spinal cord glial activation and proinflammatory cytokines . Furthermore, pain from traumatic neuropathies are created by spinal cord-brain-spinal cord loops and have also been linked to spinal cord glial activation (Colburn et al, 1999;Winkelstein et al, 2001) and proinflammatory cytokines (Arruda et al, 2000;Sweitzer et al, 2001;Winkelstein et al, 2001). Thus, although such a loop circuit may indeed exist for SIN in general and for mirror-image pain in particular, present evidence is that such a pathway would ultimately lead to spinal cord glial activation, most likely via centrifugal axonal release of substance P and excitatory amino acids Watkins and Maier, 2000).…”

“…There are three proinflammatory cytokines known to be affected by p38 MAP kinase inhibitors: TNF, IL1, and IL6 (Lee et al, 2000). All three have been implicated in the spinal mediation of pain arising from traumatic neuropathies (Arruda et al, 2000;Sweitzer et al, 2001;Winkelstein et al, 2001). Whether it is the trauma or associated inflammation of the peripheral nerve that recruits spinal proinflammatory cytokine involvement in these models is unknown.…”

Whole-body Vibration at Thoracic Resonance Induces Sustained Pain and Widespread Cervical Neuroinflammation in the Rat

“…7). Neuroinflammation is associated with pain [22,75,79], and spinal glial activation occurs after a variety of painful injuries [18,22,25,31,32,38,60,79,82,87,88,90]. The proinflammatory cytokines, IL-6 and tumor necrosis factor-a, nearly double after acceleration that was painful and occurred at the resonance of 8 Hz, like painful nerve injury [67,88,89].…”

p38 Mitogen-Activated Protein Kinase Is Activated after a Spinal Nerve Ligation in Spinal Cord Microglia and Dorsal Root Ganglion Neurons and Contributes to the Generation of Neuropathic Pain

“…Several cytokines that are released from glial cells produce pain hypersensitivity (DeLeo and Yezierski, 2001;Watkins et al, 2001a,b), and astrocytes and microglia are activated in the spinal cord after inflammation and nerve injury and in cancer models (Fu et al, 1999;Sweitzer et al, 1999;Winkelstein et al, 2001;Mantyh et al, 2002).…”