Interleukin-4 Promotes Antinociception While β-endorphin Influence Over Nociceptive Interleukin-8 Is Disrupted in TMJ Patients

Abstract

We have earlier reported that patients with chronic closed lock in the temporomandibular joint (TMJ) have increased plasma β-endorphin (βE) levels and decreased pressure pain thresholds (PPT) and increased pain scoring on a numeric rating scale (NRS) as a consequence of chronic nociceptive activity. After discectomy surgery the plasma βE and the NRS scoring of pain are decreased. The auriculotemporal nerve is at risk for irritation or entrapment between the articular fossa and the condyle which could explain TMJ pain. Inflammatory mediators, such as the cytokines, will be released. IL-8 is expressed in elevated levels in both serum and synovial fluid in chronic inflammatory joint disorders. βE may suppress IL-8 in mononuclear cells and in neutrophils. Interleukin 4 (IL-4) inhibits the hyperalgesic response to pro- inflammatory IL-8. The aims of this study were to investigate if the pain thresholds correlate with plasma cytokines in TMJ patients compared to healthy controls and to explore a balance between βE and cytokines in plasma. The PPTs were measured over the index finger and masseter muscle with an algometer in 6 patients with TMJ disc disturbances (DD) and 6 age- and sex-matched healthy controls. The electrical pain thresholds were measured over the index finger with a specific device, the PainMatcher. Venous blood samples were collected to analyze for βE and for a multiplex of 23 cytokines. Differences between the patients and the control group were tested with Mann-Whitney U test, 2-paired. The Spearman rank-correlation tests were used to investigate correlations between pain, βE, EPTs and PPTs. The patients had lower PPTs over the finger (P = .002) and over the masseter muscle (P = .002) compared to healthy controls. The EPTs over the finger were lower (P = .015) in the patient group compared to healthy controls. The plasma levels of IL- 4 and the PPTs over the finger correlated significantly in the healthy group (rs=0.828, n=6, P = .04) and in the patient group (rs=0.811, n=6, P = .049). Further, the plasma levels of IL-4 and the PPTs over the masseter muscle correlated in the healthy group (rs=0.942, P = .004) and in the patient group (rs=0.811, P = .049). The plasma levels of IL-8 and βE correlated in the healthy group (rs=0.811, P = .049) but not in the patient group (rs=−0.352, P = .493). On the contrary, there was a tendency towards a correlation between the plasma IL-8 and lower pain pressure thresholds over the masseter muscle (rs=−0.072, P = .08) in the patient group. Patients with TMJ DD have decreased PPTs and EPTs compared to healthy sex- and age-matched controls. In both groups a significant correlation was seen between IL-4 and PPTs over the finger and masseter muscle and this is referred to an antinociceptive effect of IL-4. In the healthy group the pro-inflammatory IL-8 correlated to the plasma βE levels. In the patients this correlation was absent, on the contrary, in TMJ DD IL-8 tended to be correlated to pain over masseter muscle. These findings indicate that βE is an important mediator in the balance between the nervous- and immune system.