The role of the polymorphonuclear leukocyte in hyperalgesia

Significance Persistent pain in inflammatory and neuropathic conditions is often refractory to conventional analgesic therapy, with most patients suffering with unrelieved pain and serious treatment-related side effects. There is still a tremendous need to identify novel therapeutics for pain control with innovative biological mechanisms and minimal side effects. In this paper we challenge the hypothesis that a conserved structural motif across the G protein-coupled receptor family plays a regulatory role in the negative modulation of receptor activation and use a multidisciplinary approach to the rational drug design and characterization of a novel potent allosteric inhibitor of the C5a anaphylatoxin receptor (C5aR), thus providing a new promising avenue for the improvement of pharmacotherapy of chronic pain.

Section: Discussionmentioning

confidence: 99%

Targeting the minor pocket of C5aR for the rational design of an oral allosteric inhibitor for inflammatory and neuropathic pain relief

Moriconi

Cunha

Souza

et al. 2014

“…An analgesy meter (Stoelting, Chicago), which presents a noninjurious mechanical stimulus that increases linearly with time, to the dorsum of the hindpaw, was used to measure nociceptive threshold (4,5), defined as that weight, in g, required to elicit paw withdrawal. The rats were trained in the pressure testing procedure daily for the week before gathering the reported data.…”

Section: Methodsmentioning

confidence: 99%

“…Leukotriene B4 (LTB4), derived from the 5-lipoxygenation of arachidonic acid in leukocytes and some types of epithelial cells (2,3), also evokes profound hyperalgesia on intradermal injection into the dorsum of the rat's hindpaw (4). The mechanism of hyperalgesia elicited by LTB4 is distinguished from that of PGE2 by a dependence on polymorphonuclear leukocytes (PMNLs) and a lack of effect of inhibitors of the cyclooxygenation of arachidonic acid, such as indomethacin (4,5). Furthermore, PMNLs when incubated with LTB4 in vitro release a factor that induces maximal hyperalgesia in rats that have been depleted of circulating PMNLs (5).…”

mentioning

confidence: 99%

“…Furthermore, PMNLs when incubated with LTB4 in vitro release a factor that induces maximal hyperalgesia in rats that have been depleted of circulating PMNLs (5). This hyperalgesic factor of PMNLs is a lipid of low molecular weight that coelutes on reverse-phase HPLC with the (8R, 15S)-dihydroxyicosa-(5E-9,11,13Z)-tetraenoic acid [(8R, 15S)-diHETE] product of the 15-lipoxygenation of arachidonic acid in PMNLs (5). A comprehensive study of the synthetic 8,15-diHETEs, which are products of the 15-lipoxygenation of arachidonic acid, now identifies (8R,15S)-diHETE as a hyperalgesic factor and demonstrates the antagonistic and hypoalgesic activity of (8S,15S)-dihydroxyicosa-(5E-9,11,13Z)-tetraenoic acid, [(8S,15S)-diHETE].…”

mentioning

confidence: 99%

See 1 more Smart Citation

Hyperalgesic properties of 15-lipoxygenase products of arachidonic acid.

Levine¹,

Lam²,

Taiwo³

et al. 1986

Self Cite

104

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.

“…hypernociception ͉ inflammation ͉ prokineticin receptors I n past years, several groups have generated convincing evidence that neutrophil-associated hyperalgesia results from the neutrophil release of proinflammatory pronociceptive factors, including products of arachidonic acid metabolism (1,2) and cytokines such as IL-1␤, IL-8, IL-12, TNF-␣, and macrophage inflammatory proteins MIP-1a and MIP-1b (3,4). Belonging to the chemokine family, the recently discovered prokineticins [Bv8, MIT, prokineticin 1 (PK1), and prokineticin 2 (PK2)] (5-9) activate two G protein-linked PK receptors (PKR1 and PKR2) (10)(11)(12) localized in the brain, dorsal root ganglia (DRG) neurons, granulocytes, macrophages, and endothelial cells.…”

mentioning

confidence: 99%

The chemokine Bv8/prokineticin 2 is up-regulated in inflammatory granulocytes and modulates inflammatory pain

Giannini

Lattanzi

Nicotra

et al. 2009

111

Neutrophil migration into injured tissues is invariably accompanied by pain. Bv8/prokineticin 2 (PK2), a chemokine characterized by a unique structural motif comprising five disulfide bonds, is highly expressed in inflamed tissues associated to infiltrating cells. Here, we demonstrate the fundamental role of granulocyte-derived PK2 (GrPK2) in initiating inflammatory pain and driving peripheral sensitization. In animal models of complete Freund's adjuvantinduced paw inflammation the development and duration of pain temporally correlated with the expression levels of PK2 in the inflamed sites. Such an increase in PK2 mRNA depends mainly on a marked up-regulation of PK2 gene transcription in granulocytes. A substantially lower up-regulation was also detected in macrophages. From a pool of peritoneal granulocytes, elicited in rats by oyster glycogen, we purified the GrPK2 protein, which displayed high affinity for the prokineticin receptors (PKRs) and, when injected into the rat paw, induced hypersensitivity to noxious stimuli as the amphibian prokineticin Bv8 did. Mice lacking PKR1 or PKR2 developed significantly less inflammation-induced hyperalgesia in comparison with WT mice, confirming the involvement of both PKRs in inflammatory pain. The inflammation-induced upregulation of PK2 was significantly less in pkr1 null mice than in WT and pkr2 null mice, demonstrating a role of PKR1 in setting PK2 levels during inflammation. Pretreatment with a nonpeptide PKR antagonist, which preferentially binds PKR1, dose-dependently reduced and eventually abolished both prokineticin-induced hypernociception and inflammatory hyperalgesia. Inhibiting PK2 formation or antagonizing PKRs may represent another therapeutic approach for controlling inflammatory pain.hypernociception ͉ inflammation ͉ prokineticin receptors