Reviewer's report
Title:Resolvin D1 reverses chronic pancreatitis-induced mechanical allodynia,
phosphorylation of NMDA receptors, and cytokines expression in the thoracic
spinal dorsal horn
Version: 1Date:25 May 2012
Reviewer: Ihsan Ekin Demir
Reviewer's report:
In their current study, Feng et al. investigated the potential analgesic effect of
resolvin, an omega-3-polyunsaturated fatty acid-derived molecule, in
experimental chronic pancreatitis (CP) in rats. Intrathecal administration of
resolvin (termed RvD) reduced mechanical allodynia of rats with TNBS-induced
CP, reduced the amount of IL6, TNFalpha and IL-1beta mRNA in the thoracic
spinal cord, and reversed the phosphorylation of NMDA receptor subtypes NR1
and NR2B. Based on these results, the authors concluded that resolvin may be a
novel anti-inflammatory therapeutic for the treatment of CP-associated pain.
Overall, the study conveys a straightforward message and investigated a
molecule class of high interest to treat inflammatory pain. However, despite these
clear messages within the manuscript, the provided data remain very superficial,
and the applied methodology is insufficient to support the proposed analgesic
effect of resolvin. In particular, I have the following major and minor comments:
1) Assessment of pain in murine experimental models should contain true
parameters of pain-related “behavior” and not be limited to evaluation of
mechanical allodynia, which represents a single facet of the complex “pain
phenomenon”. In line with the majority of experimental pain studies, the authors
should make use of additional tests to assess CP-related pain behavior (e.g.
open field test, elevated maze or resistance-to-capture, etc.). Without these, the
authors should refrain from referring to the effects of resolvin upon “pain
behavior” in the manuscript.
2) Although the manuscript stems from a group with experience in histological
assessment of intrinsic cells of the spinal cord in murine CP-induced pain, the
study in no way touches the affected cell type by resolvin treatment. Which cells
in the spinal cord lose their NMDA receptor phosphorylation upon resolvin
treatment? This can be easily demonstrated by phosphor-NR1/2B-specific
antibodies via immunohisto-/cytochemistry.
3) The demonstrated alterations in the level of pro-inflammatory cytokines in the
spinal cord vary between 1-2-fold, which, although statistically significant, are
very unlikely to represent biologically relevant alterations. Furthermore, the
assessment of these cytokines at RNA level does not contribute significantly
towards understanding the actual modulation of inflammation in the spinal cord
through resolvin, which seems to be the leading mechanism in resolvin-mediated
analgesia. Therefore, the investigators should measure the levels of these
cytokines at protein level.
4) In the whole manuscript, the administered drug is termed “resolvin/Rvd”,
which, however, normally designates a “class” of resolvins and contains several
resolvin subtypes. Did the authors administer one or more resolvin subtypes in
their experiments? This remains totally unclear.
Minor comments:
1) How were the dosages for Rvd chosen in the study? This is particularly
interesting seeing the large leap between the two applied dosages (10 vs. 500
ng).
2) In the methods, the authors specify that pancreatic inflammation was
histologically assessed. Were there also any differences in the severity of
intrapancreatic inflammation between treated vs. non-treated groups?
Furthermore, can resolvin also be detected in the serum and reach distant
targets other than spinal cord (e.g. pancreas)?
3) The location of NR1 and NR2B expression should be mentioned in the
abstract.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
I declare that I have no competing interests.
Reviewer's report
Title:Resolvin D1 reverses chronic pancreatitis-induced mechanical allodynia,
phosphorylation of NMDA receptors, and cytokines expression in the thoracic
spinal dorsal horn
Version: 1Date:25 May 2012
Reviewer: Ihsan Ekin Demir
Reviewer's report:
In their current study, Feng et al. investigated the potential analgesic effect of
resolvin, an omega-3-polyunsaturated fatty acid-derived molecule, in
experimental chronic pancreatitis (CP) in rats. Intrathecal administration of
resolvin (termed RvD) reduced mechanical allodynia of rats with TNBS-induced
CP, reduced the amount of IL6, TNFalpha and IL-1beta mRNA in the thoracic
spinal cord, and reversed the phosphorylation of NMDA receptor subtypes NR1
and NR2B. Based on these results, the authors concluded that resolvin may be a
novel anti-inflammatory therapeutic for the treatment of CP-associated pain.
Overall, the study conveys a straightforward message and investigated a
molecule class of high interest to treat inflammatory pain. However, despite these
clear messages within the manuscript, the provided data remain very superficial,
and the applied methodology is insufficient to support the proposed analgesic
effect of resolvin. In particular, I have the following major and minor comments:
1) Assessment of pain in murine experimental models should contain true
parameters of pain-related “behavior” and not be limited to evaluation of
mechanical allodynia, which represents a single facet of the complex “pain
phenomenon”. In line with the majority of experimental pain studies, the authors
should make use of additional tests to assess CP-related pain behavior (e.g.
open field test, elevated maze or resistance-to-capture, etc.). Without these, the
authors should refrain from referring to the effects of resolvin upon “pain
behavior” in the manuscript.
2) Although the manuscript stems from a group with experience in histological
assessment of intrinsic cells of the spinal cord in murine CP-induced pain, the
study in no way touches the affected cell type by resolvin treatment. Which cells
in the spinal cord lose their NMDA receptor phosphorylation upon resolvin
treatment? This can be easily demonstrated by phosphor-NR1/2B-specific
antibodies via immunohisto-/cytochemistry.
3) The demonstrated alterations in the level of pro-inflammatory cytokines in the
spinal cord vary between 1-2-fold, which, although statistically significant, are
very unlikely to represent biologically relevant alterations. Furthermore, the
assessment of these cytokines at RNA level does not contribute significantly
towards understanding the actual modulation of inflammation in the spinal cord
through resolvin, which seems to be the leading mechanism in resolvin-mediated
analgesia. Therefore, the investigators should measure the levels of these
cytokines at protein level.
4) In the whole manuscript, the administered drug is termed “resolvin/Rvd”,
which, however, normally designates a “class” of resolvins and contains several
resolvin subtypes. Did the authors administer one or more resolvin subtypes in
their experiments? This remains totally unclear.
Minor comments:
1) How were the dosages for Rvd chosen in the study? This is particularly
interesting seeing the large leap between the two applied dosages (10 vs. 500
ng).
2) In the methods, the authors specify that pancreatic inflammation was
histologically assessed. Were there also any differences in the severity of
intrapancreatic inflammation between treated vs. non-treated groups?
Furthermore, can resolvin also be detected in the serum and reach distant
targets other than spinal cord (e.g. pancreas)?
3) The location of NR1 and NR2B expression should be mentioned in the
abstract.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
I declare that I have no competing interests.
Please review this paper.
user
Reviewer's report
Title:Resolvin D1 reverses chronic pancreatitis-induced mechanical allodynia,
phosphorylation of NMDA receptors, and cytokines expression in the thoracic
spinal dorsal horn
Version: 1Date:25 May 2012
Reviewer: Ihsan Ekin Demir
Reviewer's report:
In their current study, Feng et al. investigated the potential analgesic effect of
resolvin, an omega-3-polyunsaturated fatty acid-derived molecule, in
experimental chronic pancreatitis (CP) in rats. Intrathecal administration of
resolvin (termed RvD) reduced mechanical allodynia of rats with TNBS-induced
CP, reduced the amount of IL6, TNFalpha and IL-1beta mRNA in the thoracic
spinal cord, and reversed the phosphorylation of NMDA receptor subtypes NR1
and NR2B. Based on these results, the authors concluded that resolvin may be a
novel anti-inflammatory therapeutic for the treatment of CP-associated pain.
Overall, the study conveys a straightforward message and investigated a
molecule class of high interest to treat inflammatory pain. However, despite these
clear messages within the manuscript, the provided data remain very superficial,
and the applied methodology is insufficient to support the proposed analgesic
effect of resolvin. In particular, I have the following major and minor comments:
1) Assessment of pain in murine experimental models should contain true
parameters of pain-related “behavior” and not be limited to evaluation of
mechanical allodynia, which represents a single facet of the complex “pain
phenomenon”. In line with the majority of experimental pain studies, the authors
should make use of additional tests to assess CP-related pain behavior (e.g.
open field test, elevated maze or resistance-to-capture, etc.). Without these, the
authors should refrain from referring to the effects of resolvin upon “pain
behavior” in the manuscript.
2) Although the manuscript stems from a group with experience in histological
assessment of intrinsic cells of the spinal cord in murine CP-induced pain, the
study in no way touches the affected cell type by resolvin treatment. Which cells
in the spinal cord lose their NMDA receptor phosphorylation upon resolvin
treatment? This can be easily demonstrated by phosphor-NR1/2B-specific
antibodies via immunohisto-/cytochemistry.
3) The demonstrated alterations in the level of pro-inflammatory cytokines in the
spinal cord vary between 1-2-fold, which, although statistically significant, are
very unlikely to represent biologically relevant alterations. Furthermore, the
assessment of these cytokines at RNA level does not contribute significantly
towards understanding the actual modulation of inflammation in the spinal cord
through resolvin, which seems to be the leading mechanism in resolvin-mediated
analgesia. Therefore, the investigators should measure the levels of these
cytokines at protein level.
4) In the whole manuscript, the administered drug is termed “resolvin/Rvd”,
which, however, normally designates a “class” of resolvins and contains several
resolvin subtypes. Did the authors administer one or more resolvin subtypes in
their experiments? This remains totally unclear.
Minor comments:
1) How were the dosages for Rvd chosen in the study? This is particularly
interesting seeing the large leap between the two applied dosages (10 vs. 500
ng).
2) In the methods, the authors specify that pancreatic inflammation was
histologically assessed. Were there also any differences in the severity of
intrapancreatic inflammation between treated vs. non-treated groups?
Furthermore, can resolvin also be detected in the serum and reach distant
targets other than spinal cord (e.g. pancreas)?
3) The location of NR1 and NR2B expression should be mentioned in the
abstract.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
I declare that I have no competing interests.
assistant