The cytokine, tumor necrosis factor α (TNFα), is now well established as a pain modulator in both the peripheral and central nervous systems [
1]. There is now mounting evidence of TNFα involvement in inflammatory, neuropathic and cancer-related pain [
2]. Several studies have shown a correlation between the level of TNFα expression and the development of allodynia or hyperalgesia [
2‐
5]. Besides increased local TNFα synthesis and release during peripheral inflammation, TNFα up-regulation has also been demonstrated in dorsal root ganglion (DRG) neurons [
6‐
8] and spinal cord [
3,
9,
10] in experimental models of peripheral neuropathy, including chronic constriction injury (CCI), L5 spinal nerve transection or sciatic nerve crush. It has been suggested that during neuropathy or peripheral inflammation TNFα could be released in the spinal cord mainly from activated glial cells [
9‐
11].
The effect of TNFα is mediated by two receptors: TNFR1 (p55) and TNFR2 (p75). Both receptors have been detected in DRG and spinal cord neurons [
12,
13]. In different peripheral neuropathy models, TNFR1/2 receptors are up-regulated in DRG neurons [
14‐
16] and TNFR1 in the spinal cord dorsal horn (DH) [
10]. Later studies localized TNFR2 expression exclusively in non-neuronal DRG cells after lipopolysaccharide (LPS) treatment [
17] or after inflammation induced by complete Freund's adjuvant (CFA) [
18]. It was recently demonstrated that TNFR2 receptors are crucial for the development of heat hyperalgesia in a cancer-related pain model in mice [
4].
Nociceptive DRG neurons express transient receptor potential vanilloid 1 (TRPV1) receptors, which are localized on their peripheral and central endings [
19]. In peripheral tissue they serve as molecular integrators of nociceptive stimuli. However, the function of spinal TRPV1 receptors is not fully understood. As temperature increases or pH decreases, which activate TRPV1 receptors in the periphery, do not occur in the spinal cord, great effort was needed to detect possible endogenous activators of central TRPV1 receptors [
20]. Recently, several lipids have been described as potential endogenous agonists of TRPV1 receptors. Most of them also activate cannabinoid receptors, similar to anandamide (AEA,
N-arachidonoylethanolamine), which was one of the first substances suggested to act as an endogenous TRPV1 receptor ligand [
21]. AEA has been shown to excite cutaneous C nociceptors via TRPV1 receptors activation and to evoke nocifensive behaviour after peripheral application
in vivo [
22]. Intrathecal AEA administration has been demonstrated to have an analgesic effect, while higher concentrations also evoke pain-related behavior [
23]. Other potential endogenous activators of TRPV1 receptors are products of lipoxygenases [
24], omega-3 polyunsaturated fatty acids [
25] or unsaturated
N-acyldopamines originally isolated from bovine striatum as
N-arachidonoyldopamine (NADA) [
26]. Further analysis of striatal extracts resulted in the identification of, among other acyldopamines,
N-oleoyldopamine (OLDA), which induces thermal hyperalgesia after intraplantar application and possesses a high potency of putative endovanilloid in mobilization of intracellular calcium in TRPV1-transfected cells [
27]. Unlike NADA, OLDA is only a weak ligand for rat CB1 receptors; but is recognized by the anandamide membrane transporter while being a poor substrate for fatty-acid amide hydrolase (FAAH) [
27]. Behavioral experiments have shown thermal hyperalgesia following intrathecal OLDA administration [
28]. Our previous electrophysiological recordings in spinal cord slices demonstrated that application of 10 μM OLDA solution increases mEPSC frequency in superficial DH neurons due to specific TRPV1 receptor activation, as demonstrated by TRPV1 antagonists (SB366791, BCTC) application [
28]. The concentration of OLDA needed to activate TRPV1 receptors decreased dramatically from 10 μM under control conditions to 0.2 μM after PKC activation, pretreatment with the inflammatory mediator bradykinin, or in a model of peripheral inflammation [
28].