**4.2.3 Bradykinin (BKN) and Kallidin (KAL)**

BKN and KAL are kinins – a group of structurally related 9-11 amino acid peptides that are produced by kallikrein-mediated enzymatic cleavage of kininogen (Coutaux et al., 2005; Riedel & Neeck, 2001; Wang et al., 2006). Kinins mediate their effects via two different G protein coupled receptors, B1 and B2, that provoke an increase in intracellular Ca2+ (Meyer et al., 2006; Zubakova et al., 2008). In normal tissue in the acute situation, BKN and KAL act via the B2 receptor. In the chronic phase of the response of tissue injury and infection, B1 receptors are expressed by BKN and KAL via this receptor (Calixto et al., 2004; Coutaux et al., 2005; Couture et al., 2001; Graven-Nielsen & Mense, 2001; McMahon et al., 2006). Interstitial muscle BKN and KAL have been suggested as algesic kinins involved in muscle pain. BKN was the first inflammatory mediator recognized to have potent hyperalgesic properties (Levine & Reichling, 1999). BKN induces pain and modifies the receptive fields of dorsal horn neurons to noxious stimuli in humans when administered in different ways (Boix et al., 2005; Meyer et al., 2006). BKN and cytokines are central factors in the link between tissue damage and inflammatory responses (Coutaux et al., 2005). Moreover, BKN is a potent vasodilatator and is increased in the interstitium of muscle during exercise (Clifford & Hellsten, 2004; Schmelz et al., 2003; Stewart & Rittweger, 2006). Animal studies have shown that BKN can both excite (i.e., algogenic) and sensitize nociceptors (Levine & Reichling, 1999; Wang et al., 2006). The present review identified four studies investigating the interstitial concentrations of BKN and/or Kallidin (Gerdle et al., 2008b; Larsson et al., 2008; Shah et al., 2008; Shah et al., 2005). The relatively small studies conducted by Shah et al. (Shah et al., 2008; Shah et al., 2005) clearly indicated that BKN was involved since increased levels of BKN in subjects with active trigger points and the levels were higher in the trapezius (with pain) than in a pain-free distant muscle. In contrast no significant differences in BKN were found between patients and controls in a field study and a laboratory study, (Gerdle et al., 2008b; Larsson et al., 2008) The difference in results between the above mentioned studies could be due to the fact that alterations in BKN might be very localized (i.e., in the trigger points) and not generally found in the aching trapezius muscle. KAL was only investigated in one study and increased in chronic trapezius myalgia but not in the trapezius of chronic WAD compared to controls (Gerdle et al., 2008b). Clearly, more pathophysiological *in vivo* studies are necessary in order to understand the roles of BKN and KAL for nociception and pain in patients with chronic pain.

### **4.2.4 Potassium**

Increased interstitial potassium levels may be related to muscle pain (Graven-Nielsen et al., 1997). Green et al., however, did not find potassium related to acute ischaemic myalgia in

Potential Muscle Biomarkers of Chronic Myalgia in Humans –

**4.5 Suggestions with respect to future studies** 

**5. Conclusion** 

**6. Acknowledgements** 

preparation of the manuscript.

**7. References** 

A Systematic Review of Microdialysis Studies 123

The fact that most studies of chronic trapezius myalgia, chronic WAD, and temporomandibular pain disorders included women is expected, as the prevalence of these conditions are higher in women. Future studies should also include groups of men with chronic muscle pain conditions. In addition, it is important to describe the patient group in detail with respect to clinically relevant examination parameters. Furthermore, systematic descriptions of the patient groups are needed that reflect pain intensity and psychological distress as well as consequences such as work participation and sick leave. A systematic description will allow a more accurate characterization of pain severity in a broad context. Most studies rely on bivariate correlations between pain descriptors such as pain intensity or pressure pain thresholds and the concentration of a certain substance. Multivariate correlation analyses and regression analyses are methods that can be used to investigate how groups of clinical examination variables, several simultaneous symptoms, and the concentrations of several biochemical substances intercorrelate. To better understand the potentially complex biochemical situation of the muscle in chronic pain conditions, it is necessary to also investigate the multivariate interrelationships between the concentrations of the investigated substances. According to ICD, the clinically used pain diagnoses are symptom diagnoses based on temporal and anatomical characteristics (e.g., chronic lumbago). Hence a certain diagnosis may include patients with different activated pathophysiological mechanisms. To identify subgroups of patients with identical pathophysiological mechanisms, it is important to use large patient groups and appropriate

statistical methods (e.g., cluster analysis and principal component analysis).

understanding of peripheral nociceptive processes in myalgia.

This systematic review found that most of the studies focused on trapezius myalgia (seven patient groups reported in ten studies), temporomanidibular pain syndromes (two patient groups reported in three studies), and fibromyalgia (two patient groups but different muscles). Relatively strong scientific support identifies 5-HT as a potential biomarker in chronic myalgia. Moderately strong scientific support identifies glutamate, pyruvate, and lactate as potential biomarkers in chronic trapezius myalgia. There is a need for larger studies of well-characterized patient groups with respect to perceived situations, symptoms, and signs so as to investigate several substances simultaneously in order to improve the

There are no conflicts of interest. No financial or personal relationships have inappropriately influenced this work. This study was supported by the Swedish Council for Working Life and Social Research (2010-0683, 2007-0760) and the Swedish Research Council (2010-2893). The funders had no role in study design, data collection and analysis, decision to publish, or

Afinowi, R., Tisdall, M., Keir, G., Smith, M., Kitchen, N., & Petzold, A. (2009). Improving the

recovery of S100B protein in cerebral microdialysis: implications for multimodal monitoring in neurocritical care. *Journal of neuroscience methods*, 181, pp. 95-99.

healthy subjects (Green et al., 2000). Repetitive work in healthy subjects may increase potassium levels (Rosendal et al., 2004a), although in the present systematic review no consistent pattern of increased potassium was found in patients with chronic trapezius myalgia (Larsson et al., 2008; Rosendal et al., 2005; Sjogaard et al., 2010) (**Table 1**) or with chronic WAD (**Table 2**).
