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Lipoxins and aspirin-triggered lipoxin inhibit inflammatory pain processing.

Svensson CI, Zattoni M, Serhan CN - J. Exp. Med. (2007)

Bottom Line: Furthermore, activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase in astrocytes, which has been indicated to play an important role in spinal pain processing, was attenuated in the presence of lipoxins.This linkage opens the possibility that lipoxins regulate spinal nociceptive processing though their actions upon astrocytic activation.Targeting mechanisms that counterregulate the spinal consequences of persistent peripheral inflammation provide a novel endogenous mechanism by which chronic pain may be controlled.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA. csvensson@ucsd.edu

ABSTRACT
Inflammatory conditions can lead to debilitating and persistent pain. This hyperalgesia reflects sensitization of peripheral terminals and facilitation of pain signaling at the spinal level. Studies of peripheral systems show that tissue injury triggers not only inflammation but also a well-orchestrated series of events that leads to reversal of the inflammatory state. In this regard, lipoxins represent a unique class of lipid mediators that promote resolution of inflammation. The antiinflammatory role of peripheral lipoxins raises the hypothesis that similar neuraxial systems may also down-regulate injury-induced spinal facilitation of pain processing. We report that the lipoxin A(4) receptor is expressed on spinal astrocytes both in vivo and in vitro and that spinal delivery of lipoxin A(4), as well as stable analogues, attenuates inflammation-induced pain. Furthermore, activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase in astrocytes, which has been indicated to play an important role in spinal pain processing, was attenuated in the presence of lipoxins. This linkage opens the possibility that lipoxins regulate spinal nociceptive processing though their actions upon astrocytic activation. Targeting mechanisms that counterregulate the spinal consequences of persistent peripheral inflammation provide a novel endogenous mechanism by which chronic pain may be controlled.

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Intravenous administration of lipoxins reduces inflammation-evoked hyperalgesia and edema. Paw withdrawal latency (PWL) is plotted versus time for the ipsilateral (ip; injected) and contralateral (c; uninjected) hind paw showing that i.v. injection of LXA4, ATLa (A and C), and aLXB4 (B and C), but not 8,9-aLXB4 (B and C), before injection of carrageenan reduces thermal hyperalgesia. HI (C) is calculated for 0–4 h. Paw thickness (D) was measured by calipers at different time points after induction of inflammation. Each time point and bar represents the mean ± SEM (n = 4–6). *, P < 0.05 as compared with vehicle (ip) measurements.
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fig1: Intravenous administration of lipoxins reduces inflammation-evoked hyperalgesia and edema. Paw withdrawal latency (PWL) is plotted versus time for the ipsilateral (ip; injected) and contralateral (c; uninjected) hind paw showing that i.v. injection of LXA4, ATLa (A and C), and aLXB4 (B and C), but not 8,9-aLXB4 (B and C), before injection of carrageenan reduces thermal hyperalgesia. HI (C) is calculated for 0–4 h. Paw thickness (D) was measured by calipers at different time points after induction of inflammation. Each time point and bar represents the mean ± SEM (n = 4–6). *, P < 0.05 as compared with vehicle (ip) measurements.

Mentions: Painful inflammatory conditions are associated with sensitization of specialized sensory neurons that compose the nociceptive (pain) pathway, leading to enhanced pain sensations in response to both noxious and nonnoxious stimuli (termed hyperalgesia and allodynia, respectively). Lipoxins have antiinflammatory actions in vivo when administered to the site of inflammation or systemically by the i.v. or oral route (for review see reference 2). To investigate whether lipoxins block pain associated with inflammation, LXA4, LXB4, and the more stable ATL analogue (ATLa) and an analogue of LXB4, (8,9)-acetylenic LXB4 (8,9-aLXB4), were administered i.v. to rats 2 min before injection of carrageenan to the hind paw. Hyperalgesia was assessed by measuring the response latency to a thermal stimulus. Typically, intraplantar injection of carrageenan results in a transient inflammation, apparent as an increase in paw volume and reddening of the skin, and hyperalgesia with an onset at 2 h that is resolved after 24 h (7, 8). Intravenous injection of 10 μg/kg LXA4 (28 nmol/kg), 10 μg/kg ATLa (24 nmol/kg) and 10 μg/kg LXB4 (28 nmol/kg), but not 10 μg/kg 8,9-aLXB4 (29 nmol/kg), had antihyperalgesic effects (Fig. 1, A and B). The withdrawal latencies were significantly longer for the inflamed paw in the LXA4-, ATLa-, and LXB4-injected animals, as compared with the vehicle-treated animals (Fig. 1, A and B), indicating that lipoxins can alter pain processing. These results were also processed for calculation of the hyperalgesic index (HI), and i.v. LXA4, ATLa, and LXB4 significantly reduced the HI for the 0–4-h time span (Fig. 1 C). Assessment of paw volume by measuring paw height with calipers applied across the highest point of the dorsum and plantar aspects of the paw revealed a reduction in carrageenan-evoked paw edema (Fig. 1 D), suggesting a local antiinflammatory action of lipoxins when this delivery route is used.


Lipoxins and aspirin-triggered lipoxin inhibit inflammatory pain processing.

Svensson CI, Zattoni M, Serhan CN - J. Exp. Med. (2007)

Intravenous administration of lipoxins reduces inflammation-evoked hyperalgesia and edema. Paw withdrawal latency (PWL) is plotted versus time for the ipsilateral (ip; injected) and contralateral (c; uninjected) hind paw showing that i.v. injection of LXA4, ATLa (A and C), and aLXB4 (B and C), but not 8,9-aLXB4 (B and C), before injection of carrageenan reduces thermal hyperalgesia. HI (C) is calculated for 0–4 h. Paw thickness (D) was measured by calipers at different time points after induction of inflammation. Each time point and bar represents the mean ± SEM (n = 4–6). *, P < 0.05 as compared with vehicle (ip) measurements.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2118737&req=5

fig1: Intravenous administration of lipoxins reduces inflammation-evoked hyperalgesia and edema. Paw withdrawal latency (PWL) is plotted versus time for the ipsilateral (ip; injected) and contralateral (c; uninjected) hind paw showing that i.v. injection of LXA4, ATLa (A and C), and aLXB4 (B and C), but not 8,9-aLXB4 (B and C), before injection of carrageenan reduces thermal hyperalgesia. HI (C) is calculated for 0–4 h. Paw thickness (D) was measured by calipers at different time points after induction of inflammation. Each time point and bar represents the mean ± SEM (n = 4–6). *, P < 0.05 as compared with vehicle (ip) measurements.
Mentions: Painful inflammatory conditions are associated with sensitization of specialized sensory neurons that compose the nociceptive (pain) pathway, leading to enhanced pain sensations in response to both noxious and nonnoxious stimuli (termed hyperalgesia and allodynia, respectively). Lipoxins have antiinflammatory actions in vivo when administered to the site of inflammation or systemically by the i.v. or oral route (for review see reference 2). To investigate whether lipoxins block pain associated with inflammation, LXA4, LXB4, and the more stable ATL analogue (ATLa) and an analogue of LXB4, (8,9)-acetylenic LXB4 (8,9-aLXB4), were administered i.v. to rats 2 min before injection of carrageenan to the hind paw. Hyperalgesia was assessed by measuring the response latency to a thermal stimulus. Typically, intraplantar injection of carrageenan results in a transient inflammation, apparent as an increase in paw volume and reddening of the skin, and hyperalgesia with an onset at 2 h that is resolved after 24 h (7, 8). Intravenous injection of 10 μg/kg LXA4 (28 nmol/kg), 10 μg/kg ATLa (24 nmol/kg) and 10 μg/kg LXB4 (28 nmol/kg), but not 10 μg/kg 8,9-aLXB4 (29 nmol/kg), had antihyperalgesic effects (Fig. 1, A and B). The withdrawal latencies were significantly longer for the inflamed paw in the LXA4-, ATLa-, and LXB4-injected animals, as compared with the vehicle-treated animals (Fig. 1, A and B), indicating that lipoxins can alter pain processing. These results were also processed for calculation of the hyperalgesic index (HI), and i.v. LXA4, ATLa, and LXB4 significantly reduced the HI for the 0–4-h time span (Fig. 1 C). Assessment of paw volume by measuring paw height with calipers applied across the highest point of the dorsum and plantar aspects of the paw revealed a reduction in carrageenan-evoked paw edema (Fig. 1 D), suggesting a local antiinflammatory action of lipoxins when this delivery route is used.

Bottom Line: Furthermore, activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase in astrocytes, which has been indicated to play an important role in spinal pain processing, was attenuated in the presence of lipoxins.This linkage opens the possibility that lipoxins regulate spinal nociceptive processing though their actions upon astrocytic activation.Targeting mechanisms that counterregulate the spinal consequences of persistent peripheral inflammation provide a novel endogenous mechanism by which chronic pain may be controlled.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA. csvensson@ucsd.edu

ABSTRACT
Inflammatory conditions can lead to debilitating and persistent pain. This hyperalgesia reflects sensitization of peripheral terminals and facilitation of pain signaling at the spinal level. Studies of peripheral systems show that tissue injury triggers not only inflammation but also a well-orchestrated series of events that leads to reversal of the inflammatory state. In this regard, lipoxins represent a unique class of lipid mediators that promote resolution of inflammation. The antiinflammatory role of peripheral lipoxins raises the hypothesis that similar neuraxial systems may also down-regulate injury-induced spinal facilitation of pain processing. We report that the lipoxin A(4) receptor is expressed on spinal astrocytes both in vivo and in vitro and that spinal delivery of lipoxin A(4), as well as stable analogues, attenuates inflammation-induced pain. Furthermore, activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase in astrocytes, which has been indicated to play an important role in spinal pain processing, was attenuated in the presence of lipoxins. This linkage opens the possibility that lipoxins regulate spinal nociceptive processing though their actions upon astrocytic activation. Targeting mechanisms that counterregulate the spinal consequences of persistent peripheral inflammation provide a novel endogenous mechanism by which chronic pain may be controlled.

Show MeSH
Related in: MedlinePlus