Pain is a complex sensation that may be protective or cause undue suffering and loss of function, depending on the circumstances. Peripheral nociceptor neurons (PNs) innervate most tissues, and express
ion channels, nocisensors, which depolarize the cell in response to intense stimuli and numerous substances. Inflamed tissues manifest inflammatory
hyperalgesia in which the threshold for
pain and the response to painful stimuli are decreased and increased, respectively. Constituents of the inflammatory milieu sensitize PNs, thereby contributing to
hyperalgesia.
Polyunsaturated fatty acids undergo enzymatic and
free radical-mediated oxygenation into an array of bioactive metabolites, oxygenated
polyunsaturated fatty acids (oxy-PUFAs), including the classic
eicosanoids. Oxy-PUFA production is enhanced during
inflammation. Pioneering studies by Vane and colleagues from the early 1970s first implicated classic
eicosanoids in the
pain associated with
inflammation. Here, we review the production and action of oxy-PUFAs that are not classic
eicosanoids, but nevertheless are produced in injured/ inflamed tissues and activate or sensitize PNs. In general, oxy-PUFAs that sensitize PNs may do so directly, by activation of nocisensors,
ion channels or GPCRs expressed on the surface of PNs, or indirectly, by increasing the production of inflammatory mediators that activate or sensitize PNs. We focus on oxy-PUFAs that act directly on PNs. Specifically, we discuss the role of
arachidonic acid-derived 12S-HpETE, HNE, ONE,
PGA2, iso-PGA2 and
15d-PGJ2, 5,6-and
8,9-EET, PGE2-G and 8R,15S-diHETE, as well as the
linoleic acid-derived 9-and
13-HODE in inducing acute nocifensive behavior and/or inflammatory
hyperalgesia in rodents. The nocisensors TRPV1, TRPV4 and TRPA1, and putative Gαs-type GPCRs are the PN targets of these oxy-PUFAs.