We examined mRNA expression of the pro-inflammatory cytokine IL-1β in the brainstem, thalamus, and prefrontal cortex in two rat models of neuropathic pain. Rats received a neuropathic injury: spared nerve injury (SNI) or chronic constriction injury (CCI), sham injury, or were minimally handled (control). Neuropathic pain-like behavior was monitored by tracking tactile thresholds. SNI-injured animals showed a robust decrease in tactile thresholds of the injured foot, while CCI-injured animals did not show tactile threshold changes. Ten or 24 days after nerve injury, IL-1β gene expression in the brain was determined by RT-PCR. IL-1β expression changes were observed mainly at 10 days after injury in the SNI animals, contralateral to the injury side, with increased expression in the brainstem and prefrontal cortex. The results indicate that neuro-immune activation in neuropathic pain conditions includes supraspinal brain regions, suggesting cytokine modulation of supraspinal circuitry of pain in neuropathic conditions. KeywordsCytokines; chronic pain; brainstem; thalamus; prefrontal cortex There is now convincing evidence that cytokine expression in the peripheral nervous system and in the spinal cord play a critical role in pain behavior in various models of neuropathic injury in rodents [1][2][3]. Accumulating evidence indicates that IL-1, a major pro-inflammatory cytokine, is involved in the modulation of nociceptive information. Most of the results reported derive from the administration of this cytokine either peripherally, intrathecally or directly into the brain, for review see [4]. Whether IL-1 induces analgesia or hyperalgesia when administered centrally seems to depend on the brain region involved and on the dose injected: lower doses cause hyperalgesia and higher doses are analgesic [5;6]. On the other hand, it has been recently reported that mice in which IL-1 signaling is impaired, show reduce basal pain sensitivity [7], and attenuated neuropathic pain behaviors by reducing mechanical allodynia and thermal hyperalgesia [8].Increased levels of IL-1 have been observed in the cerebrospinal fluid of chronic pain patients [9]. Cytokine expression in pain states has rarely been studied above the spinal cord. Even

Human brain imaging studies suggest that chronic neuropathic pain has a strong emotional component that is mediated by medial prefrontal cortex (mPFC) activity; in rodents, the mPFC is involved in emotional and cognitive aspects of behavior, including the extinction of Pavlovian fear conditioning. Together, these findings suggest that the cortex may modulate the memory trace of pain. As D-cycloserine (DCS), a partial agonist of the NMDA receptor, can enhance learning and potentiate the extinction of acquired fear, in the present study we tested its efficacy in neuropathic pain behavior. In rats with spared nerve injury (SNI), repeated daily oral administration of DCS reduced mechanical sensitivity of the injured limb in a dose-dependent manner; this effect continued for weeks after the cessation of DCS treatment. In addition, re-exposure to DCS further enhanced antinociceptive behavior. Repeated oral DCS administration also reduced cancer chemotherapy drug-induced neuropathic pain behavior. Infusions of DCS directly into the mPFC (especially within prelimbic cortex) or the amygdala (but not into thalamus, insula, or occipital cortex) acutely induced antinociception in SNI rats. The antinociceptive effect of intra-mPFC DCS infusions was mimicked by NMDA and glycine, and blocked by HA 966. In the mPFC of SNI rats, NR2B expression was down-regulated; however, this effect was reversed with repeated oral DCS. Lastly, infusions of DCS into mPFC reversed place avoidance behavior induced by mechanical stimulation of the injured paw in SNI rats. These findings indicate that limbic NMDA-mediated circuitry is involved in long-term reduction in neuropathic pain behavior.