Altered cytokine levels in the blood and cerebrospinal fluid of chronic pain patients
Introduction
Chronic pain conditions, including neuropathic pain (NP), remain a significant health care challenge because of their prevalence, as well as the limited response to current therapies, which are targeted primarily at symptoms (Berger et al., 2004, Elliot et al., 1999). NP was traditionally thought to be due primarily to traumatic injury or disease-related damage of the somatosensory nervous system (Backonja and Galer, 1998, Bridges et al., 2001, Mersky and Bogduk, 1994). While many peripheral and central neural mechanisms underlying the pathophysiology of persistent pain have been delineated, we have come to appreciate that inflammatory and immune processes can also have a facilitating influence both as mediators and indirectly through inflammation (DeLeo and Yezierski, 2001, Marchland et al., 2005, Watkins et al., 1994). Further resolution of the role of pro- and anti-inflammatory cytokines is of considerable importance across the many different types of chronic pain conditions. Diabetic painful neuropathy (DPN) and postherpetic neuralgia (PHN), which affect approximately 3 million people in America, are among the most readily recognized NP disorders, but there are even larger numbers of patients with traumatic neuralgias and small fiber neuropathies (Janig and Baron, 2006, Schmader, 2002, Wasner et al., 1998).
Following nerve damage due to trauma or disease, an acute inflammatory response frequently occurs, causing a transient state of hypersensitivity and allodynia, which is usually followed by healing and symptom resolution. For a subset of patients, however, there will be an induction and continuance of pain. Proinflammatory cytokines contribute through actions at the local site of injury and by enhancement of sensory transmission within the spinal cord, as well as through augmented release of cytokines centrally within the brain (De Jongh et al., 2003, Ignatowski et al., 1999, Sommer and Kress, 2004). For example, production of IL-1, TNF-α and IL-6 by Schwann cells is upregulated even before the arrival of infiltrating neutrophils and macrophages. The increased release of cytokines may also sensitize neighboring, undamaged peripheral nerves (Junger and Sorkin, 2000, McMahon et al., 2005). In addition, recent findings have delineated inflammatory processes at the dorsal root ganglia (Brisby et al., 2002, DeLeo et al., 2004). Immunohistochemical analysis of nerve biopsy tissue from patients with peripheral neuropathy indicated TNF-α was expressed in the surrounding blood vessels, Schwann cells, and macrophages, confirming the detection of increased mRNA for TNF-α in biopsy specimens (Empl et al., 2001, Sommer et al., 1998). In the Empel et al. paper, TNF-α levels did not differ between patients with painful and nonpainful conditions, but those with more mechanical allodynia had elevated levels of the soluble TNF receptor (sTNFr). Therefore, our a priori hypothesis was that sTNFr would be elevated, and the specific goal was to determine if increments are found consistently across a mixed group of pain patients.
Other cytokines may also be abnormal, including IL-8, which has been found to be elevated in CSF following postherpetic neuralgia (Kotani et al., 2004). IL-8 is frequently associated with the acute phase of infection and neutrophilia, and thus it was important to determine if IL-8 remains elevated beyond a period of viral reactivation. Even more interest has been generated by findings on low levels of anti-inflammatory cytokines, such as IL-10 (Bell et al., I997, George et al., 2004). Ucelyer et al. (2006) reported low circulating levels of IL-10 and IL-4 in both fibromyalgia (FM) and complex regional pain syndrome (CRPS) patients, and subsequently found IL-10 to be reduced in patients with painful neuropathies below that seen in nonpainful neuropathies (Uceyler et al., 2007). Correcting the IL-10 deficiency by administering mimetics or stimulators of IL-10 has been reported to be of some therapeutic value (Kanaan et al., 1998, Wagner et al., 1998). The prediction, therefore, was for low levels of IL-10 in the NP patients, but it was not certain if the values would correlate with symptom severity.
Our study investigated three proinflammatory cytokines, IL-1ß, TNFα and IL-6, as well as sTNFr and the receptor antagonist to IL-1 (IL1-ra), both of which are believed to moderate cytokine action (Aderka, 1996). IL-8, IL-10 and IL-12 were also assessed. Concentrations were determined in blood and CSF to evaluate peripheral and central processes, respectively. One challenge for interpreting CSF cytokine levels reported in many papers has been the limited information on healthy norms and reference values (Alexander et al., 2005, Van de Beekt et al., 2001). We were able to add to the information available on intrathecal cytokine concentrations in pain-free, healthy controls. The main goal was to discern which measures best characterize patients with distal painful non-diabetic polyneuropathy (DPPN) and post-traumatic neuralgia (PTN), including CRPS type I. These groups were selected to avoid disorders where infectious and inflammatory diseases were the primary cause of pain. A secondary aim was to determine if any cytokine measure correlated specifically with pain intensity.
Section snippets
Subjects
Fourteen patients were recruited from a local pain clinic, the University of Wisconsin Pain Treatment and Research Center (UW-PTRC). Study-related evaluation and procedures were performed at the General Clinical Research Center (GCRC) of the University of Wisconsin Hospital and Clinics. The protocol was reviewed and approved by the University of Wisconsin Health Sciences Institutional Review Board (IRB).
Inclusion criteria included being older than 18 years of age, with chronic pain from PTN,
Patient demographics and characteristics
Fourteen chronic pain patients, 7 women and 7 men, 25-to-60 years of age, were recruited. The etiologies of the pain disorders were PTN (n = 8) and DPPN (n = 6), with mean pain durations of 10.1 years (+/− 3.4), range .8–20.2 years. Demographic and clinical information, as well as medication use, are provided in Table 1. The age range of the 4 male and 4 female HC was similar to that of the patients: 22-to-55 years.
Symptoms commonly endorsed by NP patients were documented with the NPQ and NPS, and
Discussion
This assessment indicates that a subtle but significant increase in proinflammatory cytokine activity and decreased IL-10 secretion are readily detected features in chronic pain patients, observable even with a small sample size in a heterogeneous group. Both blood and intrathecal concentrations of sTNFr were significantly elevated above normal, as were CSF concentrations of IL-1ß. Conversely, IL-10, which has an anti-inflammatory action, was reduced in both compartments. It should be
Acknowledgments
This research was enabled by NIH core support of the UW General Clinical Research Center and Cancer Center (for KS). Partial support for the cytokine assays was provided by MH61083, and CLC is supported in part by several other NIH grants (AG20166, AI067518). The assistance of the GCRC nurses and assay services of Ms. A. Slukvina are gratefully acknowledged.
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