Sex differences in pain along the neuraxis

Presto, Peyton; Mazzitelli, Mariacristina; Junell, Riley; Griffin, Zach; Neugebauer, Volker

doi:10.1016/j.neuropharm.2022.109030

Cited by 44 publications

(31 citation statements)

References 204 publications

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Section: Resultsmentioning

confidence: 99%

“…Chronic pain exhibits a higher prevalence in women than in men (1). Over the past years, preclinical studies have highlighted several sexual dismorphism in pain mechanisms (33)(34)(35), notably at the amygdala level (36).,Thus, we sought to determine whether amygdala mGlu 4 activation can also modulate neuropathic pain symptoms in female mice. To that aim, we assessed the potential modulation of neuropathic pain symptoms following activation of mGlu 4 by the agonist LSP4-2022 in the right or left amygdala on female mice suffering from peripheral mononeuropathy in their left hind paw.…”

Section: Activation Of Mglu 4 In the Amygdala Also Relieves Neuropath...mentioning

confidence: 99%

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Differential reduction of neuropathic pain symptoms by mGlu₄-mediated neuromodulation of amygdala circuits

Pereira

Arias

Llebaría

et al. 2022

Preprint

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Neuropathic pain is a common health problem, resulting in exacerbated response to noxious and non noxious stimuli, as well as impaired emotional and cognitive responses. Unfortunately, neuropathic pain is also one of the most difficult pain syndromes to manage, highlighting the importance of better understanding of the brain regions and neuromodulatory mechanisms involved in its regulation. Among the many interconnected brain areas which process pain, the amygdala is known to play an important role in the integration of sensory and emotional pain signals. Here, we questioned the ability of a recently identified neuromodulatory mechanisms associated to the metabotropic glutamate receptors mGlu4in the amygdala to modulate neuropathic pain. In a murine model of peripheral mononeuropathy induced by a chronic constriction of the sciatic nerve, we demonstrate that pharmacological activation of amygdala mGlu4receptors efficiently alleviates sensory and depressive-like symptoms in both male and female mice. Moreover, we reveal a differential modulation of those symptoms, activating mGlu4receptors in the controlateral amygdala, relatively to the side of the mononeuropathy, is necessary and sufficient to relieve both sensory and depressive-like symptoms while ipsilateral activation solely reduces depressive-like symptoms. Furthermore, using photopharmacology, a recent strategy allowing a precise spatiotemporal photocontrol of deep brain endogenous targets, we further demonstrate the rapid and reversible action of mGlu4-mediated neuromodulation on neuropathic pain symptoms. Finally, coupling photopharmacology and analgesic conditioned place preference, we show an important pain-reducing effect of mGlu4 activation. Taken together, these data highlight the analgesic potential of enhancing amygdala mGlu4activity to counteract neuropathy in the hope of improving existing treatments.

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Section: Resultsmentioning

confidence: 99%

Section: Activation Of Mglu 4 In the Amygdala Also Relieves Neuropath...mentioning

confidence: 99%

Differential reduction of neuropathic pain symptoms by mGlu₄-mediated neuromodulation of amygdala circuits

Pereira

Arias

Llebaría

et al. 2022

Preprint

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“…Increasing evidence across the pain field has revealed sexually dimorphic mechanisms that contribute to pain development and maintenance (recently reviewed in Presto et al, 2022 ). Studies from the periphery and spinal cord have illustrated a male-predominant reliance on macrophage-related (Liu et al, 2020 ; Rudjito et al, 2021 ) and microglia-related (Sorge et al, 2011 , 2015 ; Taves et al, 2016 ; Agalave et al, 2021 ) pain processing mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Sex Differences in CGRP Regulation and Function in the Amygdala in a Rat Model of Neuropathic Pain

Presto

Neugebauer

2022

Front. Mol. Neurosci.

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The amygdala has emerged as a key player in the emotional response to pain and pain modulation. The lateral and capsular regions of the central nucleus of the amygdala (CeA) represent the “nociceptive amygdala” due to their high content of neurons that process pain-related information. These CeA divisions are the targets of the spino-parabrachio-amygdaloid pain pathway, which is the predominant source of calcitonin gene-related peptide (CGRP) within the amygdala. Changes in lateral and capsular CeA neurons have previously been observed in pain models, and synaptic plasticity in these areas has been linked to pain-related behavior. CGRP has been demonstrated to play an important role in peripheral and spinal mechanisms, and in pain-related amygdala plasticity in male rats in an acute arthritis pain model. However, the role of CGRP in chronic neuropathic pain-related amygdala function and behaviors remains to be determined for both male and female rats. Here we tested the hypothesis that the CGRP1 receptor is involved in neuropathic pain-related amygdala activity, and that blockade of this receptor can inhibit neuropathic pain behaviors in both sexes. CGRP mRNA expression levels in the CeA of male rats were upregulated at the acute stage of the spinal nerve ligation (SNL) model of neuropathic pain, whereas female rats had significantly higher CGRP and CGRP receptor component expression at the chronic stage. A CGRP1 receptor antagonist (CGRP 8-37) administered into the CeA in chronic neuropathic rats reduced mechanical hypersensitivity (von Frey and paw compression tests) in both sexes but showed female-predominant effects on emotional-affective responses (ultrasonic vocalizations) and anxiety-like behaviors (open field test). CGRP 8-37 inhibited the activity of CeA output neurons assessed with calcium imaging in brain slices from chronic neuropathic pain rats. Together, these findings may suggest that CGRP1 receptors in the CeA are involved in neuropathic pain-related amygdala activity and contribute to sensory aspects in both sexes but to emotional-affective pain responses predominantly in females. The sexually dimorphic function of CGRP in the amygdala would make CGRP1 receptors a potential therapeutic target for neuropathic pain relief, particularly in females in chronic pain conditions.

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“…Our results are also in line with the clinical reality which has shown that gender differences exists with respect to pain tolerance and thresholds, and that there is a higher prevalence of chronic pain conditions for females (Meints et al, 2018; Sorge and Totsch, 2017; Templeton, 2020). Finally, gender differences in pain perception and modulation exists at molecular, cellular, and system level (Presto et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

How to make calibration less painful – a proposition of an automatic, reliable and time-efficient procedure

Świder

Bruña

Moratti

2022

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Background: The description of the calibration in pain studies is scarce. This study provides an in-depth analysis and proposes an automatic pain-threshold calibration that quantifies its correctness, minimizes its duration and invasiveness, and considers validation of linearity between stimuli intensity and Numerical Rating Scale (NRS) values. Methods: 70 healthy volunteers (37 males) underwent a staircase calibration method adjusted for A-delta specific intraepidermal electrical stimulation. The sensation (t) and pain thresholds (T) intensities were calculated using: the traditional threshold method (TM), a linear regression model (LRM), and two variants of a proposed truncated LRM (tLRM). The tLRM analyses data up to an optimal point, chosen according to the maximum goodness-of-fit value (R2). The optimal value of R2 and the convergence based on the regression line gradient formed the base for rejection criteria of failed procedure. Then, we compared the different methods for thresholds assessment as well as mid-painful stimulation (MP), equivalent to 1.5*T or NRS equal to 8, using repeated measures ANOVA. Results: Four participants were rejected according to our criteria. tLRM methods exhibit higher R2 than LRM with 36% less stimuli application. Compared to other methods, tLRM result in significantly higher t and lower T and MP intensities. Last, significantly lower t and T were found for female compared to men, regardless of the calibration method. Conclusions: The proposed method of calibration reduces the number of stimuli delivered and can be easily adapted to other simulation modalities. However, future investigation is recommended using adaptive LRM fitting and verification of reliability.

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Sex differences in pain along the neuraxis

Cited by 44 publications

References 204 publications

Differential reduction of neuropathic pain symptoms by mGlu₄-mediated neuromodulation of amygdala circuits

Differential reduction of neuropathic pain symptoms by mGlu₄-mediated neuromodulation of amygdala circuits

Sex Differences in CGRP Regulation and Function in the Amygdala in a Rat Model of Neuropathic Pain

How to make calibration less painful – a proposition of an automatic, reliable and time-efficient procedure

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Sex differences in pain along the neuraxis

Cited by 44 publications

References 204 publications

Differential reduction of neuropathic pain symptoms by mGlu4-mediated neuromodulation of amygdala circuits

Differential reduction of neuropathic pain symptoms by mGlu4-mediated neuromodulation of amygdala circuits

Sex Differences in CGRP Regulation and Function in the Amygdala in a Rat Model of Neuropathic Pain

How to make calibration less painful – a proposition of an automatic, reliable and time-efficient procedure

Contact Info

Product

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Differential reduction of neuropathic pain symptoms by mGlu₄-mediated neuromodulation of amygdala circuits

Differential reduction of neuropathic pain symptoms by mGlu₄-mediated neuromodulation of amygdala circuits