**4.3 Anti-analgesic substances**

As is obvious from the above, most studies concern metabolites and algesic substances. Little is known about changes in the pain-inhibitory signalling molecules. One interesting group of such molecules is the *N*-acylethanolamines (NAEs), which is a family of endogenous lipid mediators that have several roles including the regulation of inflammation and pain (Pacher et al., 2006). Examples of NAEs are *N*-palmitoylethanolamine (PEA), Nstearoylethanolamine (SEA), N-oleoylethanolamine (OEA), and N-arachidonoylethanolamine (anandamide, AEA). The most thoroughly studied of the NAEs is AEA, which interacts with cannabinoid receptors. At higher concentrations, AEA also targets transient receptor potential (vanilloid-1) receptors and has been shown to have anti-nociceptive actions in a number of animal models of pain (Calignano et al., 1998). The present review also includes one study of SEA and PEA (Ghafouri et al., 2011), which reported significantly increased levels of two NAEs.

#### **4.4 Other pain conditions identified**

According to our review, microdialysis of painful muscles have also been investigated, but these studies have only been based on one group of patients of each condition: polymyalgia rheumatic, chronic tension-type headache, and mitochondrial myopathy. Hence no definite conclusions concerning potential biomarkers can be drawn for these conditions. The results concerning polymyalgia rheumatic were prominent for several algesics including cytokines. Kreiner et al. investigated the presence of muscle alterations (Kreiner & Galbo, 2011; Kreiner et al., 2010), and they found that the biochemical alterations were normalized after treatment with prednisolone. Although more studies are needed, their results suggest that intramuscular mechanisms are important.

In the studies of different chronic tendinosis, the number of patients was low and no consistent patterns were seen. Larger studies are needed to identify biochemical alterations.
