Monoterpenoids: The Next Frontier in the Treatment of Chronic Pain?

Round 1

Reviewer 1 Report

I think that the review is well organized about the natural compound and broad concept of pain. However, this review needs some modification. It looks like a typo correction is required. In particular, in the case of Figure 3, it is difficult to distinguish which pathological characteristics are illustrated. Also, some active agents are missing in Figure 5.

Minor

Figure2: Th17 cel (green) ->  Th17 T cells?

Figure3: This picture is unclear, which is a physiological and pathological pathway. The figure looks like a mixed pathway.

Section 3: It would be more interesting to add the results of whether these drugs differ in permeability in human and animal models.

Figure5: Because Trpv3 agonist is camphor, eugenol, carvacrol, thymol, menthol, cinnamaldehyde, and citral,  It looks like camphor is only one agonist for TRPV3 and it seems like generate the miss understating to readers.

The prolonged exposition of TRPV3 to camphor results in the desensitization of the receptor and in a diminished calcium influx.

A study demonstrated that the TRPV1 receptors hold more than one site where agonists can bind.

Is it true? I know, repeated exposure of camphor can trigger TRPV3’s sensitization and TRPV1’s desensitization

.… skin permeation and suggest a possible role in topic treatments…..

Topic ->topical? 

aminoacid

Author Response

Reviewer 1

Figure2: Th17 cel (green) ->  Th17 T cells?

Altered as requested.

Figure3: This picture is unclear, which is a physiological and pathological pathway. The figure looks like a mixed pathway.

The figure was revised and carefully described

Section 3: It would be more interesting to add the results of whether these drugs differ in permeability in human and animal models. 

Human data is discussed. Animal models are considered less important by the FDA. Differences in permeability between animal and human models has been extensively discussed in several reviews.

Figure5: Because Trpv3 agonist is camphor, eugenol, carvacrol, thymol, menthol, cinnamaldehyde, and citral,  It looks like camphor is only one agonist for TRPV3 and it seems like generate the miss understating to readers.

The information was added to the figure.

The prolonged exposition of TRPV3 to camphor results in the desensitization of the receptor and in a diminished calcium influx.

A study demonstrated that the TRPV1 receptors hold more than one site where agonists can bind.

Is it true? I know, repeated exposure of camphor can trigger TRPV3’s sensitization and TRPV1’s desensitization

The desensitization of TRPV3 after prolonged exposure to camphor was documented in “Sherkheli, Azhar & Vogt-Eisele, Angela & Weber, Kirsten & Hatt, Hanns. (2013). Camphor modulates TRPV3 cation channels activity by interacting with critical pore-region cysteine residues. Pakistan journal of pharmaceutical sciences. 26. 431-8.” as well as in “Billen, Bert & Brams, Marijke & Debaveye, Sarah & Remeeva, Alina & Alpizar, Yeranddy & Waelkens, Etienne & Kreir, Mohamed & Brueggemann, Andrea & Talavera Perez, Karel & Nilius, Bernd & Voets, Thomas & Ulens, Chris. (2015). Different Ligands of the TRPV3 Cation Channel Cause Distinct Conformational Changes As Revealed by Intrinsic Tryptophan Fluorescence Quenching. The Journal of biological chemistry. 290. 10.1074/jbc.M114.628925.”.

.… skin permeation and suggest a possible role in topic treatments….. 

Topic ->topical? 

Altered as requested.

aminoacid

Altered as requested.

Reviewer 2 Report

Major

1 In Fig1, the mechanism of nociception and peripheral sensitization mediated by PGs. The figure legend should be described clearer. For example, what are the functions of COX-1, COX-2, and 5-LOX in this fig? What do the yellow and purple circles and tetragons indicate? What do the black arrows indicate? More important is whether the PKC and PKA are activated by the activation of the PG receptor directly? All the details should be described exactly in the fig and legend.

2 In the third paragraph on page 3, the author said PGE2 blocks inhibitory glycinergic neurotransmission, as shown in Fig1. However, this inhibition was not presented in Fig1. But according to reference 12, did Prof. Woolf and Salter discussed it in their paper?

3 in each section, the paragraphs are too much to catch the points.

4 the fig4 should be present in high quality.

5 even though the authors discussed the relationship between monoterpenoids and TRP channels, many monoterpenoids, such as thymol, (-)-menthol, carvacrol, have been reported to modulate the excitatory or inhibitory transmission in spinal Lamina II via TRP channels. The authors should consider it.

Minor

1 In line 10 of the first paragraph, there is an additional comma.

2 In line 2 of the 2. The topical management of the chronic pain section, The citation of 7,8,9 should be put in the same brackets and there is an additional period.

3 in the second paragraph in The topical management of the chronic pain section, the last sentence mentioned afferent pain fibers. It is better to use nociceptors instead of pain fibers.

4 in the third paragraph on page 3, include activation…… and inhibition …… an should be added. The same minor mistakes also happened in other places.  

Author Response

Reviewer 2

Major

1 In Fig1, the mechanism of nociception and peripheral sensitization mediated by PGs. The figure legend should be described clearer. For example, what are the functions of COX-1, COX-2, and 5-LOX in this fig? What do the yellow and purple circles and tetragons indicate? What do the black arrows indicate? More important is whether the PKC and PKA are activated by the activation of the PG receptor directly? All the details should be described exactly in the fig and legend.

The figure was revised and the details were properly described in the legend.

2 In the third paragraph on page 3, the author said PGE2 blocks inhibitory glycinergic neurotransmission, as shown in Fig1. However, this inhibition was not presented in Fig1. But according to reference 12, did Prof. Woolf and Salter discussed it in their paper?

Woolf and Salter poorly mention the depression of GABA/glycinergic transmission. The sentence was hence removed and the reference to figure 1 was moved.

3 in each section, the paragraphs are too much to catch the points.

Some paragraphs were split for easier reading

4 the fig4 should be present in high quality.

Altered as requested.

5 even though the authors discussed the relationship between monoterpenoids and TRP channels, many monoterpenoids, such as thymol, (-)-menthol, carvacrol, have been reported to modulate the excitatory or inhibitory transmission in spinal Lamina II via TRP channels. The authors should consider it.

The purpose of the current review is to discuss the skin. There are several books and reviews that discuss the brain and brainstem. However, a brief discussion of this issue and a new reference have been added as requested.

Minor

1 In line 10 of the first paragraph, there is an additional comma.

Altered as requested.

2 In line 2 of the 2. The topical management of the chronic pain section, The citation of 7,8,9 should be put in the same brackets and there is an additional period.

Altered as requested.

3 in the second paragraph in The topical management of the chronic pain section, the last sentence mentioned afferent pain fibers. It is better to use nociceptors instead of pain fibers.

Altered as requested.

4 in the third paragraph on page 3, include activation…… and inhibition …… an should be added. The same minor mistakes also happened in other places.  

Altered as requested.

Round 2

Reviewer 2 Report

no