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

Abstract

Mirror-image allodynia is a mysterious phenomenon that occurs in association with many clinical pain syndromes. Allodynia refers to pain in response to light touch/pressure stimuli, which normally are perceived as innocuous. Mirror-image allodynia arises from the healthy body region contralateral to the actual site of trauma/inflammation. Virtually nothing is known about the mechanisms underlying such pain. A recently developed animal model of inflammatory neuropathy reliably produces mirror-image allodynia, thus allowing this pain phenomenon to be analyzed. In this sciatic inflammatory neuropathy (SIN) model, decreased response threshold to tactile stimuli (mechanical allodynia) develops in rats after microinjection of immune activators around one healthy sciatic nerve at mid-thigh level. Low level immune activation produces unilateral allodynia ipsilateral to the site of sciatic inflammation; more intense immune activation produces bilateral (ipsilateral ϩ mirror image) allodynia. The present studies demonstrate that both ipsilateral and mirrorimage SIN-induced allodynias are (1) reversed by intrathecal (peri-spinal) delivery of fluorocitrate, a glial metabolic inhibitor; (2) prevented and reversed by intrathecal CNI-1493, an inhibitor of p38 mitogen-activated kinases implicated in proinflammatory cytokine production and signaling; and (3) prevented or reversed by intrathecal proinflammatory cytokine antagonists specific for interleukin-1, tumor necrosis factor, or interleukin-6. Reversal of ipsilateral and mirror-image allodynias was rapid and complete even when SIN was maintained constantly for 2 weeks before proinflammatory cytokine antagonist administration. These results provide the first evidence that ipsilateral and mirror-image inflammatory neuropathy pain are created both acutely and chronically through glial and proinflammatory cytokine actions.

Do glial cells control pain?

“…Fluorocitrate has been shown to alleviate pain behavior in animal models of inflammatory pain, neuropathic pain, and postoperative pain (Clark et al, 2007a;Meller et al, 1994;Milligan et al, 2003;Obata et al, 2006;Watkins et al, 1997). However, it fails to inhibit muscle pain, a pain condition that does not show any glial activation (Ledeboer et al, 2006).…”

“…Second, drugs that target downstream common pathways such as MAPK pathways or TNF-α and IL-1β signaling (Fig. 6) could be very effective, if the side effects can be tolerated (Watkins and Maier, 2003;. p38 MAPK inhibitors show high efficacy in different animal models, but they may produce side effects when high doses or long-term treatment are employed.…”

“…Minocycline may show efficacy when given during the early phase of disease development. Propentofylline, a glial modulating agent, shows efficacy in different pain models including neuropathic pain model (Watkins and Maier., 2003;Tawfik et al, 2007). Methotrexate has recently been shown to reduce neuropathic pain and microglia activation in animals (Scholz et al, 2008).…”

Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway

“…IL-1β is upregulated in the spinal cord in different chronic pain conditions and plays an important role in pain facilitation (Sweitzer et al, 2001;Milligan et al, 2003). In a recent model of bone cancer pain in rats, which results from inoculation of the tibia with prostate cancer cells, IL-1β is induced in spinal astrocytes at certain times (Zhang et al, 2005).…”

“…These cytokines are upregulated in the spinal cord in chronic pain conditions. Functional inhibition of these cytokines can attenuate persistent pain and enhance opioid analgesia (Sweitzer et al, 2001;Watkins et al, 2001;Milligan et al, 2003;Watkins et al, 2005). However, the distinct roles of specific glial subtypes in pain sensitization were not assessed in these studies.…”