Cellular mechanisms underlying central sensitization in a mouse model of chronic muscle pain
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Evaluation Summary:
This manuscript explores the role of the central amygdala (CeA) on the mechanisms underlying chronic pain. An acid-induced muscle pain (AIMP) mouse model was used. The authors report a key pro-nociception role of CeA Somatostatin (SST) expressing neurons. The central sensitization of CeA-SST neurons was blocked by pregabalin. This work also further highlights the opposing view of the roles of CeA-SST neurons compared to CeA-PKCd neurons in modulating pain-related behaviors. This work will likely have a significant impact in the field and reconciles different previous results.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Abstract
Chronic pain disorders are often associated with negative emotions, including anxiety and depression. The central nucleus of the amygdala (CeA) has emerged as an integrative hub for nociceptive and affective components during central pain development. Prior adverse injuries are precipitating factors thought to transform nociceptors into a primed state for chronic pain. However, the cellular basis underlying the primed state and the subsequent development of chronic pain remains unknown. Here, we investigated the cellular and synaptic alterations of the CeA in a mouse model of chronic muscle pain. In these mice, local infusion of pregabalin, a clinically approved drug for fibromyalgia and other chronic pain disorders, into the CeA or chemogenetic inactivation of the somatostatin-expressing CeA (CeA-SST) neurons during the priming phase prevented the chronification of pain. Further, electrophysiological recording revealed that the CeA-SST neurons had increased excitatory synaptic drive and enhanced neuronal excitability in the chronic pain states. Finally, either chemogenetic inactivation of the CeA-SST neurons or pharmacological suppression of the nociceptive afferents from the brainstem to the CeA-SST neurons alleviated chronic pain and anxio-depressive symptoms. These data raise the possibility of targeting treatments to CeA-SST neurons to prevent central pain sensitization.
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Evaluation Summary:
This manuscript explores the role of the central amygdala (CeA) on the mechanisms underlying chronic pain. An acid-induced muscle pain (AIMP) mouse model was used. The authors report a key pro-nociception role of CeA Somatostatin (SST) expressing neurons. The central sensitization of CeA-SST neurons was blocked by pregabalin. This work also further highlights the opposing view of the roles of CeA-SST neurons compared to CeA-PKCd neurons in modulating pain-related behaviors. This work will likely have a significant impact in the field and reconciles different previous results.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
Authors' claims and conclusions are mostly well-supported by the data. A strength of the manuscript is the novel proposal of a key role for GABAergic SST+ CeA neurons in the MP model. Furthermore, chemogenetic inactivation or pharmacological inhibition of CeA-SST+ neurons by pregabalin (PGB), a selective ligand for α2δ subunit of voltage-gated calcium channels, convincingly alleviate chronic MP.
A weakness of the manuscript is that the investigation of the role of the input from the parabrachial nucleus (PBN) to the CeA should be more thorough fully investigated. Furthermore. pregabalin (PGB), is widely used in the experiments submitted, but whether PGB affects the mechano-sensitivity and emotional behavior separately is not addressed.
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Reviewer #2 (Public Review):
Previous studies, that investigated the involvement of the CeA and of its constituting neurons in central sensitization, have led to largely inconsistent results. The work described in this manuscript provides new support for a critical role of CeA SST+ neurons in the chronification of pain and of the comorbid affective behaviors. The reported shift in activity of PCK+ and SST+ neurons after the development of chronic muscle pain, that was opposite for these two neuron classes, lends additional molecular evidence for the involvement of these neurons in this process.
The ability of PGB to reduce pain and negative emotions in models of chronic pain is not new as well as its influence on excitatory postsynaptic currents in neurons of the CeA. However, the work by Lin and associates offers novel insights on how …
Reviewer #2 (Public Review):
Previous studies, that investigated the involvement of the CeA and of its constituting neurons in central sensitization, have led to largely inconsistent results. The work described in this manuscript provides new support for a critical role of CeA SST+ neurons in the chronification of pain and of the comorbid affective behaviors. The reported shift in activity of PCK+ and SST+ neurons after the development of chronic muscle pain, that was opposite for these two neuron classes, lends additional molecular evidence for the involvement of these neurons in this process.
The ability of PGB to reduce pain and negative emotions in models of chronic pain is not new as well as its influence on excitatory postsynaptic currents in neurons of the CeA. However, the work by Lin and associates offers novel insights on how PGB regulates nociceptive transmission between PBN and CeA SST+ neurons. Moreover, using in vivo Ca2+ imaging in behaving mice, the influence of PGB on CeA SST+ neurons was examined, which revealed that although a majority of the recorded cells reduced their activity in the presence of PGB, other SST+ neurons were either excited or insensitive to PGB application. This led the authors to suggest the existence of several functionally different SST+ neurons in the CeA with complex intrinsic and extrinsic connectivity.
This is a nice and well performed study that used a variety of state-of-the-art methodologies. Most of the data are well controlled and support the main conclusions. In my opinion, one shortcoming of this paper is the excessive emphasis on the effect of PGB in reducing the nociceptive and emotional manifestations of chronic muscle pain, as these have already been well studied in models of neuropathic pain. On the other hand, this study provides important new information about neuronal and synaptic dysfunctions in the CeA during priming and the development of chronic pain.In conclusion, despite the findings described in this manuscript are in general sound, a few issues, in my opinion, need to be addressed to further strengthen both the science and its presentation.
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Reviewer #3 (Public Review):
In this manuscript, the authors showed that in the chronic muscle pain (MP) model, which causes mechanical allodynia, mice also developed anxiety-like and depression-like behaviors. Slice recording data showed chronic MP increased excitatory synaptic transmission to CeA-SST and enhanced their excitability, while decreased excitatory transmission to CeA-PKCd neurons and reduced their excitability. Local CeA infusion of pregabalin (PGB) or chemogenetic inhibition of CeA-SST neurons during the priming phase can reverse the mechanical allodynia and affective phenotypes in the MP mice. Whereas increasing activity of CeA-PKCd neurons reduced mechanical hypersensitivity without changing the affective behaviors. Taken together, the authors concluded that CeA-SST as a key node for central sensitization in this model.
Reviewer #3 (Public Review):
In this manuscript, the authors showed that in the chronic muscle pain (MP) model, which causes mechanical allodynia, mice also developed anxiety-like and depression-like behaviors. Slice recording data showed chronic MP increased excitatory synaptic transmission to CeA-SST and enhanced their excitability, while decreased excitatory transmission to CeA-PKCd neurons and reduced their excitability. Local CeA infusion of pregabalin (PGB) or chemogenetic inhibition of CeA-SST neurons during the priming phase can reverse the mechanical allodynia and affective phenotypes in the MP mice. Whereas increasing activity of CeA-PKCd neurons reduced mechanical hypersensitivity without changing the affective behaviors. Taken together, the authors concluded that CeA-SST as a key node for central sensitization in this model.
This study adds to the CeA-pain research field which has revealed opposite results for CeA-SST and CeA-PKCd neurons in pain versus anti-nociception by different groups. In this regard, it shows the role of different CeA neurons in another chronic pain model and will fuel further studies by the field to reconcile the different results.
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