In Response

Our study1 found that rats with or without perioperative fentanyl injections demonstrated a significant hyperalgesia for several days after plantar incision and significant increases in proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNFα), in the spinal cord and bilateral dorsal root ganglia (DRG) but not in cerebrospinal fluid (CSF). The main reason that we assayed IL-1β and TNFα in CSF was to find an explanation for why the proinflammatory cytokines significantly increased in contralateral DRG as well as the ipsilateral DRG. The lack of translatable IL-1β and TNFα in CSF suggested that the increase of proinflammatory cytokines in contralateral DRG might be the connection between spinal microglia and DRG by cellular junction or other unclear mechanism rather than proinflammatory cytokines diffused into CSF. Our study did not eliminate the possibility that other cytokines, chemokines, or neurotrophic factors may diffuse into CSF and may contribute to the increase of proinflammatory cytokines in contralateral DRG after treatments. Dr Srinivas2 suggested that an efflux component may develop immediately after treatments and explain the increase of proinflammatory cytokines in contralateral DRG. We agree that it might happen. However, we collected the spinal cord, DRG, and CSF samples almost at the same time. Second, the increase of proinflammatory cytokines in the spinal cord was significant and persistent. If proinflammatory cytokines in the spinal cord diffused into CSF sufficiently, we should have detected them in CSF, but we did not detect any change of cytokines concentrations in CSF after treatments. This may imply that the cellular junction between spinal microglia and DRG may be a reasonable route, although the true mechanism is unclear. Inflammation, trauma, drug, or various diseases may induce an increase of proinflammatory cytokines, chemokines, or neurotrophic factors in the spinal cord or brain, along with pain behavior in animals.1,3 However, if we want to use cytokines such as IL-1β, IL-6, or TNFα as biomarkers for predicting and diagnosing pain in patients, we must collect CSF or blood as a sample for assay. A comprehensive review3 demonstrated that some proinflammatory cytokines increased in CSF in patients suffering from chronic pain, for example, a significant increase of IL-6 in lumbar radiculopathy patients, an increase of IL-8 in postherpetic neuralgia patients, and upregulation of IL-6, IL-8, and prostaglandin E2 in CSF after major orthopedic surgery. It also suggested that these changes correlated with pain severity and/or pain duration and that cytokines in the CSF could serve as biomarkers for predicting and diagnosing chronic or postoperative pain.3 However, the results were not always consistent in the same disease. Lundborg et al4 demonstrated an increased IL-8 in both CSF and blood, an increased IL-1β in CSF, and an increased IL-6 in blood in osteoarthritis patients. However, the study by Yeager et al5 demonstrated no significant differences of IL-6 level between osteoarthritis patients and healthy patients in CSF and blood. Thus, we are not yet able to use specific inflammatory factors as biomarkers to diagnose and prognose pain. Haihua Shu, PhD, MDLu Chang, MDDepartment of AnesthesiologyGuangdong Second Provincial General HospitalGuangzhou, Guangdong, China[email protected]