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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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Intrathecal injection of lipoxins reduces inflammation-evoked hyperalgesia. Paw withdrawal latency (PWL) is plotted versus time for the left ipsilateral (ip) and contralateral (c) hind paw, showing that i.t. pretreatment (−2 min) with equimolar doses of LXA4 (A and C), LXB4, and ATLa and a higher dose of 8,9-aLXB4 (B and C), as well as posttreatment with LXA4 (injection at 120 min or at 120 min followed by a second injection at 190 min; E and F), reduces inflammation-evoked hyperalgesia. HI is calculated for 0–4 h (C) and 2–6 h (F). None of the i.t.-delivered lipoxins altered paw thickness (D). Each time point and bar represents the mean ± SEM (n = 6–8). *, P < 0.05 as compared with vehicle (ip) measurements.
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fig2: Intrathecal injection of lipoxins reduces inflammation-evoked hyperalgesia. Paw withdrawal latency (PWL) is plotted versus time for the left ipsilateral (ip) and contralateral (c) hind paw, showing that i.t. pretreatment (−2 min) with equimolar doses of LXA4 (A and C), LXB4, and ATLa and a higher dose of 8,9-aLXB4 (B and C), as well as posttreatment with LXA4 (injection at 120 min or at 120 min followed by a second injection at 190 min; E and F), reduces inflammation-evoked hyperalgesia. HI is calculated for 0–4 h (C) and 2–6 h (F). None of the i.t.-delivered lipoxins altered paw thickness (D). Each time point and bar represents the mean ± SEM (n = 6–8). *, P < 0.05 as compared with vehicle (ip) measurements.

Mentions: Peripheral inflammation triggers release of factors such as PGs not only at the site of inflammation but also in the spinal cord (9). It is important to note that PGs not only have proinflammatory actions but can also drive the initiation of the resolution phase via PGE2 and PGD2 actions on PMN that include the induction of lipoxygenases that enable the formation of lipoxins (10). This led us to investigate whether spinal (intrathecal [i.t.])-administrated lipoxins have an antihyperalgesic effect. Peripheral afferents innervating the lower hind limbs, including the paws, terminate at the lumbar level of the spinal cord. To enable local delivery of lipoxins, injection catheters were implanted so that the tip of the catheter was placed at the level of the lumbar spinal cord. Although i.t. injection of the vehicle (saline) had no effect on carrageenan-induced hyperalgesia, i.t. LXA4 (0.3 nmol) attenuated the carrageenan-evoked hyperalgesia in a dose-dependent fashion (Fig. 2, A and C), and equimolar dosing of ATLa had a similar effect (Fig. 2 C). On the contrary, i.t. LXA4 did not alter normal nociceptive thresholds, as indicated by the lack of change in withdrawal latency of the contralateral (uninflamed) paw (Fig. 2 A). Intrathecal injection of the positional isomer LXB4 (0.3 nmol) also caused antihyperalgesia, whereas a higher dose of 8,9-aLXB4 (10 nmol) was required for similar effects (Fig. 2, B and C). None of the lipoxins altered carrageenan-induced paw edema (Fig. 2 D). The therapeutic potential of lipoxins was tested by i.t. injection of LXA4 at time points when the carrageenan-induced hyperalgesia was established. Although a single dose of LXA4 (0.3 nmol) showed a modest effect, two consecutive injections resulted in a statistically significant reversal of the hyperalgesia (Fig. 2, E and F). To examine whether the antihyperalgesic effect of i.t.-delivered lipoxins is caused by redistribution, the same dose of LXA4 that was effective when injected i.t. was administered i.v. Intravenous administration of 0.3 nmol LXA4 did not reduce carrageenan-evoked thermal hyperalgesia or peripheral inflammation (Fig. 1 A), and it is thus unlikely that the effect observed with spinal administration of lipoxins is the result of redistribution from the spinal compartment to the site of inflammation. Because the trihydroxytetraene structure of native lipoxins is sensitive to metabolic inactivation by dehydrogenation, LXA4 was administered via continuous i.t. infusion that resulted in a prolonged antihyperalgesic effect compared with i.t. bolus injection (Fig. S1, available at http://www.jem.org/cgi/content/full/jem.20061826/DC1). These results suggest that lipoxins have antinociceptive action not only after systemic delivery but also when delivered spinally, and that the antihyperalgesiceffect exerted at the spinal level is mediated via a mechanism that is distinct from regulation of peripheral inflammation and edema.


Lipoxins and aspirin-triggered lipoxin inhibit inflammatory pain processing.

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

Intrathecal injection of lipoxins reduces inflammation-evoked hyperalgesia. Paw withdrawal latency (PWL) is plotted versus time for the left ipsilateral (ip) and contralateral (c) hind paw, showing that i.t. pretreatment (−2 min) with equimolar doses of LXA4 (A and C), LXB4, and ATLa and a higher dose of 8,9-aLXB4 (B and C), as well as posttreatment with LXA4 (injection at 120 min or at 120 min followed by a second injection at 190 min; E and F), reduces inflammation-evoked hyperalgesia. HI is calculated for 0–4 h (C) and 2–6 h (F). None of the i.t.-delivered lipoxins altered paw thickness (D). Each time point and bar represents the mean ± SEM (n = 6–8). *, P < 0.05 as compared with vehicle (ip) measurements.
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Related In: Results  -  Collection

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fig2: Intrathecal injection of lipoxins reduces inflammation-evoked hyperalgesia. Paw withdrawal latency (PWL) is plotted versus time for the left ipsilateral (ip) and contralateral (c) hind paw, showing that i.t. pretreatment (−2 min) with equimolar doses of LXA4 (A and C), LXB4, and ATLa and a higher dose of 8,9-aLXB4 (B and C), as well as posttreatment with LXA4 (injection at 120 min or at 120 min followed by a second injection at 190 min; E and F), reduces inflammation-evoked hyperalgesia. HI is calculated for 0–4 h (C) and 2–6 h (F). None of the i.t.-delivered lipoxins altered paw thickness (D). Each time point and bar represents the mean ± SEM (n = 6–8). *, P < 0.05 as compared with vehicle (ip) measurements.
Mentions: Peripheral inflammation triggers release of factors such as PGs not only at the site of inflammation but also in the spinal cord (9). It is important to note that PGs not only have proinflammatory actions but can also drive the initiation of the resolution phase via PGE2 and PGD2 actions on PMN that include the induction of lipoxygenases that enable the formation of lipoxins (10). This led us to investigate whether spinal (intrathecal [i.t.])-administrated lipoxins have an antihyperalgesic effect. Peripheral afferents innervating the lower hind limbs, including the paws, terminate at the lumbar level of the spinal cord. To enable local delivery of lipoxins, injection catheters were implanted so that the tip of the catheter was placed at the level of the lumbar spinal cord. Although i.t. injection of the vehicle (saline) had no effect on carrageenan-induced hyperalgesia, i.t. LXA4 (0.3 nmol) attenuated the carrageenan-evoked hyperalgesia in a dose-dependent fashion (Fig. 2, A and C), and equimolar dosing of ATLa had a similar effect (Fig. 2 C). On the contrary, i.t. LXA4 did not alter normal nociceptive thresholds, as indicated by the lack of change in withdrawal latency of the contralateral (uninflamed) paw (Fig. 2 A). Intrathecal injection of the positional isomer LXB4 (0.3 nmol) also caused antihyperalgesia, whereas a higher dose of 8,9-aLXB4 (10 nmol) was required for similar effects (Fig. 2, B and C). None of the lipoxins altered carrageenan-induced paw edema (Fig. 2 D). The therapeutic potential of lipoxins was tested by i.t. injection of LXA4 at time points when the carrageenan-induced hyperalgesia was established. Although a single dose of LXA4 (0.3 nmol) showed a modest effect, two consecutive injections resulted in a statistically significant reversal of the hyperalgesia (Fig. 2, E and F). To examine whether the antihyperalgesic effect of i.t.-delivered lipoxins is caused by redistribution, the same dose of LXA4 that was effective when injected i.t. was administered i.v. Intravenous administration of 0.3 nmol LXA4 did not reduce carrageenan-evoked thermal hyperalgesia or peripheral inflammation (Fig. 1 A), and it is thus unlikely that the effect observed with spinal administration of lipoxins is the result of redistribution from the spinal compartment to the site of inflammation. Because the trihydroxytetraene structure of native lipoxins is sensitive to metabolic inactivation by dehydrogenation, LXA4 was administered via continuous i.t. infusion that resulted in a prolonged antihyperalgesic effect compared with i.t. bolus injection (Fig. S1, available at http://www.jem.org/cgi/content/full/jem.20061826/DC1). These results suggest that lipoxins have antinociceptive action not only after systemic delivery but also when delivered spinally, and that the antihyperalgesiceffect exerted at the spinal level is mediated via a mechanism that is distinct from regulation of peripheral inflammation and edema.

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