Pathophysiology of Nociception and Rare Genetic Disorders with Increased Pain Threshold or Pain Insensitivity

Round 1

Reviewer 1 Report

This review paper summarizes the research related to the rare genetic disorders that can reduce or totally suppress pain sensitivity. The paper is generally well written and merits publication; however, the quality of the paper can be enhanced if the following points can be addressed.

 

1. I suggest the authors to add a little more background to the diseases and conditions that can lead to reduced or absent pain seensitivity  (eg.CIPA) in the introduction.

2. There is always a dilemma on how to conclude a review article. Since the authors have deliberately summarized huge amounts of published results, it will go a long way. It would be helpful if they can provide their own thoughts that would in turn help in finding the areas that need to be addressed. For example, what are the factors that one needs to consider while choosing an ideal gene for pain suppression, For clinical transformation of these genes what steps need to be taken?

Author Response

Manuscript ID: pathophysiology-1809879

 

Dear Editor,

 

Thank you for giving us the opportunity to submit a further revised draft of our manuscript titled:

 

Nociception and rare genetic disorders featuring reduced or absent pain sensitivity

 

We appreciate the time and effort that you and the reviewers have dedicated to providing your valuable feedback on our manuscript. We are grateful to the reviewers for their insightful comments.

We have been able to incorporate changes to reflect most of the suggestions provided by the reviewers and we have highlighted the changes within the manuscript.

 

Here is a point-by-point response to the reviewers’ comments and concerns.

 

Reviewer 1

 

This review paper summarizes the research related to the rare genetic disorders that can reduce or totally suppress pain sensitivity. The paper is generally well written and merits publication; however, the quality of the paper can be enhanced if the following points can be addressed.

 

1. I suggest the authors to add a little more background to the diseases and conditions that can lead to reduced or absent pain seensitivity (eg.CIPA) in the introduction.

 

Response: thank you for your suggestions. We revised the Introduction and highlighted this paramount aspect.

 

2. There is always a dilemma on how to conclude a review article. Since the authors have deliberately summarized huge amounts of published results, it will go a long way. It would be helpful if they can provide their own thoughts that would in turn help in finding the areas that need to be addressed. For example, what are the factors that one needs to consider while choosing an ideal gene for pain suppression, For clinical transformation of these genes what steps need to be taken?

 

Response: thank you for your suggestions. We revised the Conclusion. 

Reviewer 2 Report

This comment regards the manuscript titled "Nociception and rare genetic disorders featuring reduced or absent pain sensitivity". The manuscript is a revision discussing genetic disorders characterized by increased pain threshold or pain insensitivity.  The authors also describe the nociceptor characteristics and my comments to be addressed are listed as follow:

Introduction:

- In Introduction section, rare desorder is not mentioned, but it is written in title. If the authors write it on title, one expect these type of disorder (HSAN, chromosomal abnormalities, etc.) been mentioned in introduction. Please, provide one or two paragraph introducing these points.

- In page 2, lines 72-74: The main objective of the present manuscript is to "discuss genetic disorders characterized by increased pain threshold or pain insensitivity". However, the conclusion section describes nociception and low or absent pain perception or pain insensitivity. Why the authors not conclude about increased pain threshold? If it is an objective of the manuscript, this topic should be addressed in conclusion.

Material and Methods:

- Does the authors made a quantification of number of published articles by year (e.g, 10 articles in 2005, 15 articles in 2006, 20 articles in 2007, etc.)? If they did, does the quantity of published articles increases through years? If yes, I suggest the authors to make a table or bar chart with this quantification, to strenght the relevance of this review article.

- page 2, lines 79-80: Please clarify the exclusion criterion, because "published in peer-reviewed scientific journals" are presented in both inclusion and exclusion criterion.

- In 2.1 Search strategy, the authors say "We researched the PubMed database using keywords or combinations of keywords", bu what type of boolean operator they used? Please state it in this section.

- In 2.2 Study selection, line 92-93: The initial quantity of articles were 450, but from those, 189 were selected and discussed. What was the criterion to exclude the other 261 articles? Note that english language and published in peer-reviewed scientific journals were the initial procedures to achieve the 450 articles.

Results:

- In page 3, lines 101-103: Including DRG and Trigeminal ganglia, did the authors find other ganglia with nociceptors? The visceras and part of gastrointestinal system also have vagal afferents innervation and its cell body are located in nodose ganglia (NG), but ir remains unclear if the neurons in NG conveys nociceptive sensation. Although not clear, since this is a review manuscript, I suggest the authors to address this point.

- Table 1: There is a range of axonal conduction velocities in each type of sensory receptor. Add this range. Also, add the references for the information in this table.

- In figure 1, lines 202-203: In this phrase, if receptor are associated to the nociceptor in free nerve ending, thus the ionic current generated will modify the voltage response, not the action potential, in the nerve ending potential. Thus, I suggest to modify the pharse "...its characteristics action potential (intensity (mV).." to "its characteristics voltage response (intensity (mV)..."

- In page 7, line 229, please remove the words "chapter of";

Research and Perspectives:

- The authors highlight the Nav 1.7, but gain-of-function of Nav 1.9 was also described in the review. What type of perspectives the authors could discuss to this type of channel? Yet, the receptor tyrosine receptor kinase A could be get some attention in this section.

Author Response

Dear Reviewer, we have greatly appreciated your comments and suggestions.

Reviewer 2

 

Comment. This comment regards the manuscript titled "Nociception and rare genetic disorders featuring reduced or absent pain sensitivity". The manuscript is a revision discussing genetic disorders characterized by increased pain threshold or pain insensitivity.  The authors also describe the nociceptor characteristics and my comments to be addressed are listed as follow:

 

Introduction:

 

- In Introduction section, rare desorder is not mentioned, but it is written in title. If the authors write it on title, one expect these type of disorder (HSAN, chromosomal abnormalities, etc.) been mentioned in introduction. Please, provide one or two paragraph introducing these points.

 

Response: Thank you for your comment. Notably, the other reviewer highlighted the same issue. We added sentences in Introduction section.

 

Comment

 

- In page 2, lines 72-74: The main objective of the present manuscript is to "discuss genetic disorders characterized by increased pain threshold or pain insensitivity". However, the conclusion section describes nociception and low or absent pain perception or pain insensitivity. Why the authors not conclude about increased pain threshold? If it is an objective of the manuscript, this topic should be addressed in conclusion.

 

Response: we agree with the underlined gap and the section (Conclusion) was revised.

 

Material and Methods:

 

- Does the authors made a quantification of number of published articles by year (e.g, 10 articles in 2005, 15 articles in 2006, 20 articles in 2007, etc.)? If they did, does the quantity of published articles increases through years? If yes, I suggest the authors to make a table or bar chart with this quantification, to strenght the relevance of this review article.

 

Response: A bar chart was included. It indicates the annual trend of the selected papers (Figure 1)

 

- page 2, lines 79-80: Please clarify the exclusion criterion, because "published in peer-reviewed scientific journals" are presented in both inclusion and exclusion criterion.

 

Response: As publishing in peer-reviewed scientific journals was an inclusion criterion, we revised the text.

 

- In 2.1 Search strategy, the authors say "We researched the PubMed database using keywords or combinations of keywords", but what type of boolean operator they used? Please state it in this section.

 

- In 2.2 Study selection, line 92-93: The initial quantity of articles were 450, but from those, 189 were selected and discussed. What was the criterion to exclude the other 261 articles? Note that english language and published in peer-reviewed scientific journals were the initial procedures to achieve the 450 articles.

 

Response: we agree with these comments. Nevertheless, this paper was not a systematic review, and only a dataset was searched. The string we adopted derived from a combination of terms. 261 articles was not considered as out of the scope for this narrative review.

 

Results:

 

- In page 3, lines 101-103: Including DRG and Trigeminal ganglia, did the authors find other ganglia with nociceptors? The visceras and part of gastrointestinal system also have vagal afferents innervation and its cell body are located in nodose ganglia (NG), but ir remains unclear if the neurons in NG conveys nociceptive sensation. Although not clear, since this is a review manuscript, I suggest the authors to address this point.

 

Response: we STRONGLY agree. It was a very useful comment.

 

 

- Table 1: There is a range of axonal conduction velocities in each type of sensory receptor. Add this range. Also, add the references for the information in this table.

 

Response: references and ranges were provided in the table.

 

- In figure 1, lines 202-203: In this phrase, if receptor are associated to the nociceptor in free nerve ending, thus the ionic current generated will modify the voltage response, not the action potential, in the nerve ending potential. Thus, I suggest to modify the pharse "...its characteristics action potential (intensity (mV).." to "its characteristics voltage response (intensity (mV)..."

 

Response: we corrected it as suggested

 

- In page 7, line 229, please remove the words "chapter of";

 

Response: we corrected it as suggested

 

Research and Perspectives:

 

- The authors highlight the Nav 1.7, but gain-of-function of Nav 1.9 was also described in the review. What type of perspectives the authors could discuss to this type of channel? Yet, the receptor tyrosine receptor kinase A could be get some attention in this section.

 

Response: both issues were addressed

 

Round 2

Reviewer 2 Report

The authors answered my comments satisfactorily and made efforts to insert the suggestions in the manuscript. Congratulations.

Author Response

Thank you for your comments