Hyperalgesic properties of 15-lipoxygenase products of arachidonic acid.

Abstract

Induction of hyperalgesia by leukotriene B4 (LTB4), a potent chemotactic factor for polymorphonuclear leukocytes (PMNLs), depends on the generation by cutaneous PMNLs of mediators that are probably derived from the 15-lipoxygenation of arachidonic acid. The capacity of dihydroxyicosatetraenoic acid (diHETE) products of the 15-lipoxygenation of arachidonic acid in PMNL to elicit hyperalgesia was evaluated by assessing the effects of intradermal injection of synthetic diHETEs on the pressure nociceptive threshold in rats. (8R,15S)-Dihydroxyicosa-(5E-9,11,13Z)-tetraenoic acid [(8R,15S)-diHETE] produced a dosedependent hyperalgesia, as measured by decrease in threshold for paw withdrawal. The isomer (8S,15S)-diHETE antagonized in a dose-dependent manner this hyperalgesia due to (8R,15S)-diHETE but did not suppress prostaglandin E2-induced hyperalgesia. (8S,15S)-DiHETE produced a dose-dependent hypoalgesia, as reflected by an increase in nociceptive threshold, suggesting a contribution ofendogenous (8R,1SS)-diHETE to normal nociceptive threshold. The hypoalgesic effect of (8S,15S)-diHETE was blocked by corticosteroids but not by the cyclooxygenase inhibitor indomethacin. Neither (8R,15S)-dihydroxyicosa-(5,13E-9,11Z)-tetraenoic acid nor (8R,15S)-dihydroxyicosa-(5,11E-9,13Z)-tetraenoic acid exhibited any hyperalgesic or hypoalgesic activity. The stereospecificity ofthe effect of (8R,15S)-diHETE suggests that the induction of hyperalgesia is a receptor-dependent phenomenon and that (8S,15S)-diHETE may be an effective receptor-directed antagonist. The (8R,15S)-diHETE and (8S,15S)-diHETE from PMNL, keratinocytes, and other epithelial cells may modulate normal primary afferent function and contribute to inflammatory hyperalgesia.

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

“…In vitro treatment of polymorphonuclear leukocytes with LTB 4 led to release of a factor that produced hyperalgesia in rats depleted of these cells and appeared to be identical with the 15-LOX product, 8(R),15(S)-di-HETE (421). Subsequently, 8(R),15(S)-di-HETE was also shown to induce mechanical hyperalgesia with a short onset latency similar to PGE 2 (422,695). The hyperalgesic effect of LTB 4 had a markedly longer onset latency, suggesting that it acts by stimulating leukocytes to release 8(R),15(S)-di-HETE which eventually sensitizes nociceptors.…”

Pathogenesis of Degenerative Joint Disease in the Human Temporomandibular Joint

“…Prostaglandins, specifically PGE 2 , have been identified in lavage fluids obtained during arthroscopic examinations of human temporomandibular joints (Quinn and Bazan, 1990). Prostaglandins may lower the sensitivity threshold for primary afferent neurons in affected regions of the joint, producing pain with stimuli that are normally innocuous (i.e., normal joint movements) (Levine et al, 1986;Levine and Taiwo, 1990;White et al, 1991;Deworetal, 1992).…”

Direct activation of capsaicin receptors by products of lipoxygenases: Endogenous capsaicin-like substances

“…Products of lipoxygenases (LOs) have been implicated in mediating inflammatory nociception because various LO products are produced during inflammation (9) and cause hyperalgesia when injected intradermally (10,11). In addition, products of LOs often function as intracellular messengers in neurons.…”