Light-based tools have transformed modern biology. Beyond the established biomolecular detection and visualization technologies (Rodriguez et al., 2017; Wu and Shroff, 2022), recent developments use light as a control element to direct the activity of cells and biomolecules in vitro and in vivo (Szobota and Isacoff, 2010). The strategic introduction of chromophores as light-responsive molecular elements in cells has resulted in a precise regulation of biological function with high spatial, temporal, and biochemical precision. After light absorption, the chromophore undergoes chemical changes that modify the structure and function of the receptor and can be reversibly activated and deactivated.

Photopharmacology (or optopharmacology) is an innovative technique that combines the use of light and photoresponsive molecules to obtain precise spatiotemporal control of drug activity (Paoletti et al., 2019; Hüll et al., 2018; Frank et al., 2015; López-Cano et al., 2023). As such, in vivo photopharmacology has emerged as a unique approach to identifying mechanisms of drug actions and as the doorway to precision medicine (Hüll et al., 2018; Fuchter, 2020; Velema et al., 2014). Using light-sensitive drugs, it is possible to optimize the efficacy of new therapeutic agents and minimize their adverse effects resulting from widespread actions after systemic administration. The use of photopharmacology-based approaches to interrogate receptors in the brain is attractive due to the possibilities of manipulating the activity of specific localizations during defined times (Kramer et al., 2013; Matera and Bregestovski, 2022).

Photopharmacological approaches have recently been explored for pain modulation by members of our team (Font et al., 2017; Notartomaso et al., 2022; Pereira et al., 2023) and by others (Ma et al., 2023; Landra-Willm et al., 2023). The drug treatment of neuropathic pain, i.e., chronic pain originating from damage or disease of the somatosensory system, remains a major therapeutic challenge and unmet medical need because of severe side effects and a high percentage of patients resistant to medication (Fornasari, 2017; Finnerup et al., 2015). Neuropathic pain reflects the development of neuroplasticity that drives nociceptive sensitization, i.e., the amplification of pain signal transmission in most stations of the pain neuraxis, including regions of the pain matrix that encode the perceptive and emotional-affective components of pain (Latremoliere and Woolf, 2009; Carozzi et al., 2008; Colloca et al., 2017). Targeting glutamate receptors represents a potential strategy aimed at restraining the maladaptive form of synaptic plasticity associated with chronic pain, and photomolecular tools directed at glutamate (Levitz et al., 2017) receptors have been developed combining chemical and genetic techniques.

A large body of evidence suggests that type-5 metabotropic glutamate (mGlu5) receptors are candidate drug targets for the treatment of neuropathic pain. mGlu5 receptors, which belong to group-I mGlu receptors, are coupled to G_q/11 proteins, and their activation leads to polyphosphoinositide (PI) hydrolysis, with the ensuing formation of inositol-1,4,5-trisphosphate and diacylglycerol (Nicoletti et al., 2011). mGlu5 receptors are widely expressed in most regions of the pain neuraxis and can contribute to the development of nociceptive sensitization. Pharmacological blockade of mGlu5 receptors has mostly shown antinociceptive activity in preclinical models of inflammatory and neuropathic pain (Mazzitelli et al., 2022; Nicoletti et al., 2015). In contrast, oral administration of a mGlu5 receptor-negative allosteric modulator (NAM, fenobam), had minimal temporary analgesic effects and no clinically or statistically significant persistent analgesic effect on heat/capsaicin-induced cutaneous hyperalgesia in healthy volunteers (Cavallone et al., 2020). It remains to be determined if, and to what extent, region-specific actions are involved in the analgesic activity of mGlu5 receptor NAMs, considering that opposing actions have been reported (Chung et al., 2018; Kiritoshi et al., 2016).

To address this question, we applied photopharmacology to identify brain region-specific functions of mGlu5 in neuropathic pain, using the well-established chronic constriction injury (CCI) model (Bennett and Xie, 1988). We designed a new experimental strategy that combined the systemic application of photocaged, or photoswitchable compounds with their optical activation, silencing or reactivation in specific brain regions. We tested two functionally distinct light-sensitive mGlu5 receptor ligands: (i) a caged derivative of the mGlu5 receptor NAM raseglurant (compound JF-NP-26), which is inactive on its own and activated by light in the visible spectrum (405 nm) Font et al., 2017; and, (ii) the photoswitchable mGlu5 receptor NAM alloswitch-1, which is active on its own, is inactivated by light at 405 nm, and can be re-activated by light at 520 nm (Pittolo et al., 2014).

The use of light allows a highly restricted spatio-temporal control of drug activity without genetic manipulation of targeted receptor proteins (as opposed to optogenetics). In addition, light in the visible spectrum does not damage CNS tissue and can be delivered multiple times if needed. The use of photoactive drugs also allows an extremely rapid control of pain, circumventing the anatomical barrier that limits the access of analgesic agents to their target sites. For example, light-induced activation of JF-NP-26 in the thalamus caused rapid and robust analgesia in a mouse model of breakthrough cancer pain, a sudden severe, and transient type of pain that may develop in cancer patients under treatment with opioids (Notartomaso et al., 2022). Light-activation of JF-NP-26 can help identify the site within the pain neuraxis where mGlu5 receptor blockade is sufficient to cause analgesia. In contrast, light-inactivation of alloswitch-1 allows to establish the region where mGlu5 receptor blockade is necessary for the induction of analgesia. In combination with electrophysiological analyses, the photopharmacological approach can shed light on the functional circuit controlling pain and other nervous system functions in response to the activation of mGlu5 receptors.

For brain region-specific optical activation and inactivation of mGlu5 NAMs to determine the site of action of mGlu5 receptors, we selected prefrontal cortical (infralimbic, prelimbic and anterior cingulate cortices) and subcortical (thalamus and amygdala) regions that have been implicated in sensory, affective and cognitive aspects of pain and pain modulation (Colloca et al., 2017; Neugebauer et al., 2023). This study shows that prefrontal cortical regions and thalamus are necessary and sufficient for the antinociceptive effects of mGlu5 receptor blockade by systemic NAMs in neuropathic pain conditions. Unexpectedly, however, local mGlu5 receptor inhibition in the basolateral amygdala produced pronociceptive rather than antinociceptive effects by blocking feedforward inhibition of the central nucleus of amygdala without affecting amygdala output to prelimbic cortex (see Figure 4). Thus, the use of light-sensitive drugs allowed the demonstration of a heterogenous function of mGlu5 receptors in the pain neuraxis, which may have important implications for the application of precision medicine in the treatment of chronic pain.

The aim of this study was to determine the region-specific behavioral and electrophysiological effects of mGlu5 receptor blockade with caged and photoswitchable NAMs in neuropathic pain using photopharmacology. While the effect of optical manipulations of photosensitive mGlu5 NAMs in individual brain regions in pain models has been studied before (Font et al., 2017; Notartomaso et al., 2022; Gómez-Santacana et al., 2017), the comparative analysis across different brain regions and their contribution to systemically applied NAMs represents a novel concept.

mGlu5 receptor signaling in brain regions of the pain matrix in neuropathic pain

Mice with chronic constriction injury (CCI) of the left sciatic nerve showed the expected hypersensitivity reflected in the decrease of mechanical pain thresholds measured in the ipsilateral hind paw after 16 days (Figure 1a and b). We examined mGlu5 receptor signaling in regions of the contralateral pain matrix using an in vivo method for the assessment of mGlu5-receptor-mediated PI hydrolysis (Zuena et al., 2018). Mice were pretreated with lithium ions and then challenged with a selective mGlu5 receptor-positive allosteric modulator (PAM, VU0360172, 30 mg/kg, i.p.). mGlu5-mediated PI hydrolysis (i.e. the extent of VU0360172-stimulated InsP formation) was amplified in the contralateral infralimbic cortex, prelimbic cortex, anterior cingulate cortex, and basolateral amygdala (BLA), but not in the contralateral ventrobasal thalamus (VPL), of CCI mice compared to the corresponding regions of sham-operated mice (Figure 1c–g). mGlu5 receptor protein levels were up-regulated in the contralateral infralimbic cortex, but not in other brain regions, of CCI mice (Figure 1—figure supplement 1). The findings suggest that mGlu5 receptors become hyperactive at least in four regions of the pain matrix after induction of neuropathic pain.

Figure 1 with 1 supplement see all

Download asset Open asset

Figure 1—source data 1

Neuropathic pain model and mGlu5 receptor signaling in different brain regions.

https://cdn.elifesciences.org/articles/94931/elife-94931-fig1-data1-v1.zip

Download elife-94931-fig1-data1-v1.zip

Optical modulation of mGlu5 receptors

We applied photopharmacology to study brain region-specific functions and pharmacological manipulations of mGlu5 receptors by implanting optic fibers in the contralateral infralimbic cortex, prelimbic cortex, anterior cingulate cortex, amygdala (BLA), and thalamus (VPL) of CCI and sham mice 12 days after surgery (Figure 2a and b). Four days later, mice received a systemic injection of JF-NP-26 (10 mg/kg, i.p.), alloswitch-1 (10 mg/kg, i.p.), or their respective vehicle (Figure 2b, i and o). JF-NP-26 is an inactive pro-drug of the mGlu5 receptor NAM raseglurant and can be activated by blue-violet light (405 nm) (Font et al., 2017). The trans-isomer of alloswitch-1 is a systemically active mGlu5 receptor NAM, which can be isomerized into inactive cis-alloswitch-1 by blue-violet light (405 nm) and converted back into the active trans-isomer by green light (520 nm) (Pittolo et al., 2014; Figure 2c).

Figure 2 with 3 supplements see all

Download asset Open asset

Figure 2—source data 1

Behavioral effects of light-induced manipulations of mGlu5 receptors in different brain regions in CCI mice.

https://cdn.elifesciences.org/articles/94931/elife-94931-fig2-data1-v1.zip

Download elife-94931-fig2-data1-v1.zip

Neural circuity underlying the antinociceptive effects of mGlu5 blockade in the prelimbic cortex

To understand the neural basis for the antinociceptive behavioral effects of optical modulation of alloswitch-1 in the medial prefrontal cortex, we conducted whole-cell patch-clamp electrophysiological recordings from pyramidal neurons in layer 5 of the prelimbic cortex in brain slices from CCI mice 16 days post-injury. Excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) were evoked in visually identified pyramidal neurons by stimulation of presumed afferents from BLA that traverse the infralimbic cortex in layer 4 (Figure 3a–c), as described previously (Ji et al., 2010). EPSCs and IPSCs were blocked by bath application of a glutamate receptor antagonist (CNQX, 20 µM) confirming glutamatergic EPSCs and glutamate-driven IPSCs that are part of a feedforward inhibitory circuitry from the BLA to regulate prefrontal cortical output (Neugebauer et al., 2023; Ji et al., 2010) (IPSCs were additionally blocked by bicuculline, not shown). Synaptic responses were measured before (in artificial cerebrospinal fluid, ASCF) and during the application of alloswitch-1 to the brain slice, and during blue-violet and green light illumination to inactivate and reactivate, respectively, alloswitch-1 (Figure 3d and e).

Figure 3 with 1 supplement see all

Download asset Open asset

Figure 3—source data 1

Electrophysiological effects of light-induced manipulations of mGlu5 on prelimbic pyramidal neurons and on amygdala feed-forward inhibition in neuropathic pain.

https://cdn.elifesciences.org/articles/94931/elife-94931-fig3-data1-v1.zip

Download elife-94931-fig3-data1-v1.zip

Administration of mGlu5 NAM alloswitch-1 (100 nM) increased EPSCs compared to predrug ACSF values. Alloswitch-1 inactivation with blue-violet light (5 min, 0.5 Hz, 500 ms) slightly decreased EPSCs so that they were not significantly different from baseline values. Reactivation of alloswitch-1 with green light (5 min, 0.5 Hz, 500 ms) led to a significant increase in EPSCs compared to predrug (Figure 3d and f). No significant effects were observed on IPSCs (Figure 3e and g). As a result, the E/I ratio showed a pattern that reflected the changes in EPSCs with increases by alloswitch-1 and by reactivation with green light, and no change from baseline during blue-violet light application to inactivate alloswitch-1 (Figure 3h). These results suggest that mGlu5 receptor controls the excitatory drive of prelimbic output neurons, possibly by activation of synaptic inhibition of excitatory inputs; and mGlu5 receptor inhibition restores the excitatory drive-in neuropathic pain.

To explore if the antinociceptive behavioral effects of mGlu5 receptor inhibition in the prelimbic cortex could be explained by engaging descending pain control systems as a consequence of increased excitatory drive and output, we performed in vivo single-unit recordings of so-called ON-cells in the rostroventromedial medulla (RVM). RVM ON-cells are a critical element of top-down control of pain modulation and serve pronociceptive functions (Chen and Heinricher, 2022). Systemic administration of alloswitch-1 (10 mg/kg, i.p.) caused a trend towards decreased excitation of ON cells. Optical inactivation of alloswitch-1 in the prelimbic cortex increased ON-cell excitation whereas reactivation of alloswitch-1 with green light decreased excitation (Figure 3—figure supplement 1). The effect size of optical modulation in the prelimbic cortex on RVM activity, according to Cohen’s d calculation from t-tests, is shown in the Table 1 (see Supplementary file 1).

These results suggest that increased prelimbic cortical output with mGlu receptor inhibition (brain slice physiology data) can decrease excitation of pronociceptive RVM ON-cells resulting in antinociceptive behavioral effects (see Figure 3—figure supplement 1). These findings highlight the importance of prefrontal cortical-RVM connectivity in mediating the pain-relieving effects associated with mGlu5 receptor inhibition in the prelimbic cortex.

This photopharmacological study significantly advances our understanding of brain region-specific mGlu5 receptor function in pain modulation. To the best of our knowledge, this is the first study to employ photopharmacological tools to compare and contrast distinct roles of mGlu5 receptors in different regions of the pain matrix.

The net effect of systemic administration of alloswitch-1 was the enhancement of pain thresholds, which is in line with findings obtained with other mGlu5 receptor NAMs in models of neuropathic pain (Lax et al., 2014; Jacob et al., 2009), indicating that the overall effect of the drug across its target regions within the pain neuraxis is the induction of analgesia. However, the combined use of mGlu5 NAMs JF-NP-26 (which is activated by blue-violet light) and alloswitch-1 (which is inactivated by blue-violet light and re-activated by green light) showed for the first time that responses to mGlu5 receptor blockade are not homogenous in different regions of the pain matrix. Increases in pain thresholds after local activation of JF-NP-26 in a specific brain region indicate that mGlu5 receptor blockade in that region is sufficient for the induction of analgesia. In contrast, loss of analgesia after local inactivation of allowitch-1 suggests that mGlu5 receptor blockade in that region is necessary for the overall behavioral effect of a systemic mGlu5 receptor NAM. This innovative approach allowed us to uncover the heterogeneity and complexity of mGlu5 receptor blockade in pain processing, providing valuable insights into the underlying mechanisms of neuropathic pain. By using precise spatial control of mGlu5 receptor function, we were able to dissect the contributions of specific brain regions to the overall analgesic response.

We found that mGlu5 receptor blockade in the contralateral ventrobasal thalamus and infralimbic and prelimbic subregions of the medial prefrontal cortex (mPFC) was sufficient for the induction of analgesia and was also required for the analgesic activity of a systemically administered mGlu5 receptor NAM (Figure 2). Blockade of mGlu5 receptors in these regions resulted in increased pain thresholds, indicating their crucial involvement in the analgesic response. Conversely, selective optical inactivation of systemic alloswitch-1 in the infralimbic and prelimbic cortices and thalamus blocked the analgesic effect. This observation is particularly remarkable, considering that alloswitch-1 remained active and blocked mGlu5 receptors in all other regions of the pain system. These data suggest that regulation of pain thresholds by mGlu5 receptors in the ventrobasal thalamus and the two more ventral mPFC subregions is not redundant, but rather complementary, and that a connection between these three regions is a main target for systemic mGlu5 NAMs in the induction of analgesia in models of neuropathic pain. Nociceptive sensitization has been consistently associated with hypoactivity of pyramidal neurons in the prelimbic cortex, and activation of pyramidal neurons causes analgesia in models of neuropathic pain (Chung et al., 2018). A simplistic hypothesis is that alloswitch-1 or light-activated JF-NP-26 caused analgesia by antagonizing mGlu5 receptors expressed by inhibitory interneurons, or by excitatory neurons that preferentially activate inhibitory interneurons, within the local circuit (Chung et al., 2018). In contrast, light-induced inactivation of allowitch-1 in the contralateral anterior cingulate cortex did not abrogate the analgesic activity of the drug. While mGlu5 receptor blockade in the anterior cingulate cortex was not necessary for the overall analgesic effect of systemically administered mGlu5 NAM, antinociceptive effects of mGlu5 receptor blockade with JF-NP-26 in that region suggest that it plays a significant role in modulating pain behaviors.

There are contrasting reports on the role of mPFC mGlu5 receptors in pain modulation (Chung et al., 2018; Kiritoshi et al., 2016; Ji and Neugebauer, 2014; David-Pereira et al., 2016; Palazzo et al., 2014; Giordano et al., 2012). For example, the application of mGlu5 receptor antagonists in the ipsilateral prelimbic and infralimbic cortices enhanced neuropathic pain (spared nerve injury) (Giordano et al., 2012), whereas ipsilateral infralimbic application reduced arthritis-induced pain (David-Pereira et al., 2016) and bilateral application in prelimbic cortex caused antinociception in the spinal nerve ligation model of neuropathic pain (Chung et al., 2017). Our photopharmacological tools allowed us to establish that pharmacological blockade of mGlu5 receptors in the contralateral mPFC caused antinociception in the CCI model of neuropathic pain, and that prelimbic and infralimbic regions, but not anterior cingulate cortex, play a critical role in mediating systemic mGlu5 NAM antinociception. Our electrophysiological in vivo recordings provide evidence for the control of pro-nociceptive ON-cells in the RVM by prelimbic output (Figure 3—figure supplement 1) that is decreased by mGlu5 receptor inhibition (reinstating the local effects of alloswitch-1 in the prelimbic cortex) in neuropathic pain. Accordingly, our ex vivo brain slice physiology experiments found increased excitatory drive onto prelimbic pyramidal cells (Figure 3). Interestingly, blockade of mGlu5 in the thalamus also inhibited pain behaviors (Figure 2), possibly through projections to cortical regions such as somatosensory and insular cortices, with the latter projecting strongly to the prelimbic cortex (Dixsaut and Gräff, 2022). Previous studies showed increased mGlu5 receptor expression in the mPFC ipsilateral, but not contralateral, to peripheral nerve injury (Chung et al., 2017). We used an in vivo method to measure the primary signal transduction mechanism of mGlu5 receptors, i.e., polyphosphoinositide (PI) hydrolysis. The method was based on a pre-treatment with lithium ions (to block the conversion of inositol phosphate, InsP, into free inositol) followed by systemic activation of mGlu5 receptors with a selective PAM (VU0360172) and measurements of InsP accumulation. We found that mGlu5 receptor-mediated PI hydrolysis was significantly amplified in all subregions of the contralateral mPFC and in the contralateral amygdala after induction of neuropathic pain whereas mGlu5 receptor protein levels were significantly increased only in the contralateral infralimbic cortex of neuropathic mice (Figure 1; Figure 1—figure supplement 1). This suggests that, at least in the anterior cingulate cortex, prelimbic cortex, and basolateral amygdala, mGlu5 receptors become hyperactive after the induction of pain. It remains to be determined if this is mediated by the enhanced coupling of mGlu5 receptors to G_q/11 proteins, increased expression of phospholipase-Cβ, or other mechanisms. Interestingly, mGlu5 receptor signaling was down-regulated in the thalamus of neuropathic mice, but mGlu5 blockade in the thalamus still had antinociceptive effects (see below). Down-regulation of mGlu5 receptor signaling in the thalamus might represent a compensatory mechanism aimed at mitigating pain in neuropathic mice.

By elucidating the regional specificity of mGlu5 receptor modulation, this study expands our understanding of the neural circuitry involved in pain processing (Figure 4). Our findings have implications for the development of targeted therapies for pain management. Selective modulation of mGlu5 receptor activity in the infralimbic and prelimbic cortex presents an intriguing opportunity to harness their specific analgesic effects while minimizing potential side effects associated with global mGlu5 receptor blockade. The differential roles of mPFC regions in pain modulation highlight their unique contributions to the complex pain circuitry. Targeting the infralimbic and prelimbic cortices allows for a more precise and localized approach, potentially reducing the risk of off-target effects and enhancing the therapeutic efficacy of mGlu5 receptor-based interventions. This selective modulation strategy holds promise for the development of targeted and personalized treatments for neuropathic pain, offering a potential avenue for improved pain management with reduced adverse effects. Future research aimed at elucidating the specific mechanisms underlying the analgesic effects of mGlu5 receptor modulation in these cortices will pave the way for the development of novel therapeutic interventions and optimization of pain management strategies.

Figure 4

Download asset Open asset

A somewhat surprising finding of our study was the unique role of the amygdala (BLA) in mGlu5 function in neuropathic pain. Photopharmacology revealed for the first time that the BLA is a voice out of the chorus in the modulation of pain by mGlu5 receptors in neuropathic mice. Light-induced activation of JF-NP-26 in the right BLA reduced pain thresholds in neuropathic mice, indicating pro-nociceptive effects, whereas light-induced inactivation of alloswitch-1 in the BLA further enhanced analgesia (Figure 2). We also found that JF-NP-26 activation in the BLA decreased risk-taking behavior in neuropathic mice, consistent with increased anxiety (Figure 4). This suggests that mGlu5 receptors in BLA neurons serve antinociceptive functions in neuropathic pain, and this may limit the overall effect of mGlu5 NAMs in the treatment of pain. One possible explanation we considered is that mGlu5 receptors in the BLA modulate connections with the prelimbic and infralimbic cortices. These connections involve direct excitation as well as feedforward inhibition, and previous studies showed that electrical stimulation of BLA neurons enhanced inhibition of prelimbic neurons (Guida et al., 2017; Ishikawa and Nakamura, 2003) and decreased excitation/inhibition balance in pain resulted in impaired mPFC output and behavioral control (Kiritoshi et al., 2016; Cheriyan and Sheets, 2020). Therefore, mGlu5 NAM could be pronociceptive by decreasing the excitation/inhibition balance of BLA inputs to prelimbic regions. Results from our in vivo electrophysiological experiments, however, do not support this hypothesis (Figure 3—figure supplement 1). Instead, our ex vivo brain slice physiology studies found that mGlu5 NAM decreased feedforward inhibition of neurons in the CeA, an important output region for behavioral modulation (Neugebauer, 2020; Figure 3). Impaired feedforward inhibition of CeA output neurons drives pain behaviors (Ren et al., 2013). The role of mGlu5 function in the amygdala appears to be complex. Our data suggest pronociceptive effects of mGlu5 NAM in BLA through connections with CeA, whereas previous studies reported antinociceptive effects of mGlu5 receptor blockade with MPEP in the CeA in inflammatory pain models (Han and Neugebauer, 2005; Kolber et al., 2010). Administration of alloswitch-1 into CeA also decreased hypersensitivity in an inflammatory pain model (Ricart-Ortega et al., 2020). Interestingly, a mGlu5 antagonist (MTEP) inhibited both excitatory and inhibitory transmission in CeA neurons under normal conditions and in an arthritis pain model (Ren and Neugebauer, 2010). Thus, differential mGlu5 function in BLA and CeA may serve to shed light onto the intricate amygdala circuitry involved in pain processing and pain modulation.

In summary, the application of photopharmacology to the analysis of mGlu5 function in pain discovered novel region-specific differential actions that need to be considered when targeting these receptors as novel and improved therapeutic targets, and this may have implications for other transmitter and modulator systems.

All data needed to evaluate the conclusions in the paper are presented in the paper and/or the Supplementary Materials, and have been provided as excel files.

1. 1. Barbaro NM
   2. Heinricher MM
   3. Fields HL

   (1986) Putative pain modulating neurons in the rostral ventral medulla: reflex-related activity predicts effects of morphine

   Brain Research 366:203–210.

   https://doi.org/10.1016/0006-8993(86)91296-5

   • PubMed
   • Google Scholar
2. 1. Bennett GJ
   2. Xie YK

   (1988) A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man

   Pain 33:87–107.

   https://doi.org/10.1016/0304-3959(88)90209-6

   • PubMed
   • Google Scholar
3. 1. Boccella S
   2. Guida F
   3. De Logu F
   4. De Gregorio D
   5. Mazzitelli M
   6. Belardo C
   7. Iannotta M
   8. Serra N
   9. Nassini R
   10. de Novellis V
   11. Geppetti P
   12. Maione S
   13. Luongo L

   (2019) Ketones and pain: unexplored role of hydroxyl carboxylic acid receptor type 2 in the pathophysiology of neuropathic pain

   FASEB Journal 33:1062–1073.

   https://doi.org/10.1096/fj.201801033R

   • PubMed
   • Google Scholar
4. 1. Carozzi V
   2. Marmiroli P
   3. Cavaletti G

   (2008) Focus on the role of Glutamate in the pathology of the peripheral nervous system

   CNS & Neurological Disorders Drug Targets 7:348–360.

   https://doi.org/10.2174/187152708786441876

   • PubMed
   • Google Scholar
5. 1. Cavallone LF
   2. Montana MC
   3. Frey K
   4. Kallogjeri D
   5. Wages JM
   6. Rodebaugh TL
   7. Doshi T
   8. Kharasch ED
   9. Gereau RW

   (2020) The metabotropic glutamate receptor 5 negative allosteric modulator fenobam: pharmacokinetics, side effects, and analgesic effects in healthy human subjects

   Pain 161:135–146.

   https://doi.org/10.1097/j.pain.0000000000001695

   • PubMed
   • Google Scholar
6. 1. Chaplan SR
   2. Bach FW
   3. Pogrel JW
   4. Chung JM
   5. Yaksh TL

   (1994) Quantitative assessment of tactile allodynia in the rat paw

   Journal of Neuroscience Methods 53:55–63.

   https://doi.org/10.1016/0165-0270(94)90144-9

   • PubMed
   • Google Scholar
7. 1. Chen Q
   2. Heinricher MM

   (2022) Shifting the balance: How top-down and bottom-up input modulate pain via the rostral ventromedial medulla

   Frontiers in Pain Research 3:932476.

   https://doi.org/10.3389/fpain.2022.932476

   • PubMed
   • Google Scholar
8. 1. Cheriyan J
   2. Sheets PL

   (2020) Peripheral nerve injury reduces the excitation-inhibition balance of basolateral amygdala inputs to prelimbic pyramidal neurons projecting to the periaqueductal gray

   Molecular Brain 13:100.

   https://doi.org/10.1186/s13041-020-00638-w

   • PubMed
   • Google Scholar
9. 1. Chung G
   2. Kim CY
   3. Yun YC
   4. Yoon SH
   5. Kim MH
   6. Kim YK
   7. Kim SJ

   (2017) Upregulation of prefrontal metabotropic glutamate receptor 5 mediates neuropathic pain and negative mood symptoms after spinal nerve injury in rats

   Scientific Reports 7:9743.

   https://doi.org/10.1038/s41598-017-09991-8

   • PubMed
   • Google Scholar
10. 1. Chung G
    2. Kim SJ
    3. Kim SK

    (2018) Metabotropic glutamate receptor 5 in the medial prefrontal cortex as a molecular determinant of pain and ensuing depression

    Frontiers in Molecular Neuroscience 11:376.

    https://doi.org/10.3389/fnmol.2018.00376

    • PubMed
    • Google Scholar
11. 1. Colloca L
    2. Ludman T
    3. Bouhassira D
    4. Baron R
    5. Dickenson AH
    6. Yarnitsky D
    7. Freeman R
    8. Truini A
    9. Attal N
    10. Finnerup NB
    11. Eccleston C
    12. Kalso E
    13. Bennett DL
    14. Dworkin RH
    15. Raja SN

    (2017) Neuropathic pain

    Nature Reviews. Disease Primers 3:17002.

    https://doi.org/10.1038/nrdp.2017.2

    • PubMed
    • Google Scholar
12. 1. David-Pereira A
    2. Puga S
    3. Gonçalves S
    4. Amorim D
    5. Silva C
    6. Pertovaara A
    7. Almeida A
    8. Pinto-Ribeiro F

    (2016) Metabotropic glutamate 5 receptor in the infralimbic cortex contributes to descending pain facilitation in healthy and arthritic animals

    Neuroscience 312:108–119.

    https://doi.org/10.1016/j.neuroscience.2015.10.060

    • PubMed
    • Google Scholar
13. 1. Dixsaut L
    2. Gräff J

    (2022) Brain-wide screen of prelimbic cortex inputs reveals a functional shift during early fear memory consolidation

    eLife 11:e78542.

    https://doi.org/10.7554/eLife.78542

    • PubMed
    • Google Scholar
14. 1. Fields HL
    2. Heinricher MM

    (1985) Anatomy and physiology of a nociceptive modulatory system

    Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 308:361–374.

    https://doi.org/10.1098/rstb.1985.0037

    • PubMed
    • Google Scholar
15. 1. Finnerup NB
    2. Attal N
    3. Haroutounian S
    4. McNicol E
    5. Baron R
    6. Dworkin RH
    7. Gilron I
    8. Haanpää M
    9. Hansson P
    10. Jensen TS
    11. Kamerman PR
    12. Lund K
    13. Moore A
    14. Raja SN
    15. Rice ASC
    16. Rowbotham M
    17. Sena E
    18. Siddall P
    19. Smith BH
    20. Wallace M

    (2015) Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis

    The Lancet. Neurology 14:162–173.

    https://doi.org/10.1016/S1474-4422(14)70251-0

    • PubMed
    • Google Scholar
16. 1. Font J
    2. López-Cano M
    3. Notartomaso S
    4. Scarselli P
    5. Di Pietro P
    6. Bresolí-Obach R
    7. Battaglia G
    8. Malhaire F
    9. Rovira X
    10. Catena J
    11. Giraldo J
    12. Pin JP
    13. Fernández-Dueñas V
    14. Goudet C
    15. Nonell S
    16. Nicoletti F
    17. Llebaria A
    18. Ciruela F

    (2017) Optical control of pain in vivo with a photoactive mGlu5 receptor negative allosteric modulator

    eLife 6:23545.

    https://doi.org/10.7554/eLife.23545

    • Google Scholar
17. 1. Fornasari D

    (2017) Pharmacotherapy for neuropathic pain: A review

    Pain and Therapy 6:25–33.

    https://doi.org/10.1007/s40122-017-0091-4

    • PubMed
    • Google Scholar
18. 1. Frank JA
    2. Moroni M
    3. Moshourab R
    4. Sumser M
    5. Lewin GR
    6. Trauner D

    (2015) Photoswitchable fatty acids enable optical control of TRPV1

    Nature Communications 6:7118.

    https://doi.org/10.1038/ncomms8118

    • PubMed
    • Google Scholar
19. 1. Fuchter MJ

    (2020) On the promise of photopharmacology using photoswitches: a medicinal chemist’s perspective

    Journal of Medicinal Chemistry 63:11436–11447.

    https://doi.org/10.1021/acs.jmedchem.0c00629

    • PubMed
    • Google Scholar
20. 1. Giordano C
    2. Cristino L
    3. Luongo L
    4. Siniscalco D
    5. Petrosino S
    6. Piscitelli F
    7. Marabese I
    8. Gatta L
    9. Rossi F
    10. Imperatore R
    11. Palazzo E
    12. de Novellis V
    13. Di Marzo V
    14. Maione S

    (2012) TRPV1-dependent and -independent alterations in the limbic cortex of neuropathic mice: impact on glial caspases and pain perception

    Cerebral Cortex 22:2495–2518.

    https://doi.org/10.1093/cercor/bhr328

    • PubMed
    • Google Scholar
21. 1. Gómez-Santacana X
    2. Pittolo S
    3. Rovira X
    4. Lopez M
    5. Zussy C
    6. Dalton JAR
    7. Faucherre A
    8. Jopling C
    9. Pin J-P
    10. Ciruela F
    11. Goudet C
    12. Giraldo J
    13. Gorostiza P
    14. Llebaria A

    (2017) Illuminating phenylazopyridines to photoswitch metabotropic glutamate receptors: from the flask to the animals

    ACS Central Science 3:81–91.

    https://doi.org/10.1021/acscentsci.6b00353

    • PubMed
    • Google Scholar
22. 1. Guida F
    2. Boccella S
    3. Iannotta M
    4. De Gregorio D
    5. Giordano C
    6. Belardo C
    7. Romano R
    8. Palazzo E
    9. Scafuro MA
    10. Serra N
    11. de Novellis V
    12. Rossi F
    13. Maione S
    14. Luongo L

    (2017) Palmitoylethanolamide reduces neuropsychiatric behaviors by restoring cortical electrophysiological activity in a mouse model of mild traumatic brain injury

    Frontiers in Pharmacology 8:95.

    https://doi.org/10.3389/fphar.2017.00095

    • PubMed
    • Google Scholar
23. 1. Guida F
    2. Turco F
    3. Iannotta M
    4. De Gregorio D
    5. Palumbo I
    6. Sarnelli G
    7. Furiano A
    8. Napolitano F
    9. Boccella S
    10. Luongo L
    11. Mazzitelli M
    12. Usiello A
    13. De Filippis F
    14. Iannotti FA
    15. Piscitelli F
    16. Ercolini D
    17. de Novellis V
    18. Di Marzo V
    19. Cuomo R
    20. Maione S

    (2018) Antibiotic-induced microbiota perturbation causes gut endocannabinoidome changes, hippocampal neuroglial reorganization and depression in mice

    Brain, Behavior, and Immunity 67:230–245.

    https://doi.org/10.1016/j.bbi.2017.09.001

    • PubMed
    • Google Scholar
24. 1. Han JS
    2. Neugebauer V

    (2005) mGluR1 and mGluR5 antagonists in the amygdala inhibit different components of audible and ultrasonic vocalizations in a model of arthritic pain

    Pain 113:211–222.

    https://doi.org/10.1016/j.pain.2004.10.022

    • Google Scholar
25. 1. Hüll K
    2. Morstein J
    3. Trauner D

    (2018) In vivo photopharmacology

    Chemical Reviews 118:10710–10747.

    https://doi.org/10.1021/acs.chemrev.8b00037

    • PubMed
    • Google Scholar
26. 1. Ishikawa A
    2. Nakamura S

    (2003) Convergence and interaction of hippocampal and amygdalar projections within the prefrontal cortex in the rat

    The Journal of Neuroscience 23:9987–9995.

    https://doi.org/10.1523/JNEUROSCI.23-31-09987.2003

    • PubMed
    • Google Scholar
27. 1. Jacob W
    2. Gravius A
    3. Pietraszek M
    4. Nagel J
    5. Belozertseva I
    6. Shekunova E
    7. Malyshkin A
    8. Greco S
    9. Barberi C
    10. Danysz W

    (2009) The anxiolytic and analgesic properties of fenobam, a potent mGlu5 receptor antagonist, in relation to the impairment of learning

    Neuropharmacology 57:97–108.

    https://doi.org/10.1016/j.neuropharm.2009.04.011

    • PubMed
    • Google Scholar
28. 1. Ji G
    2. Sun H
    3. Fu Y
    4. Li Z
    5. Pais-Vieira M
    6. Galhardo V
    7. Neugebauer V

    (2010) Cognitive impairment in pain through amygdala-driven prefrontal cortical deactivation

    The Journal of Neuroscience 30:5451–5464.

    https://doi.org/10.1523/JNEUROSCI.0225-10.2010

    • PubMed
    • Google Scholar
29. 1. Ji G
    2. Neugebauer V

    (2012) Modulation of medial prefrontal cortical activity using in vivo recordings and optogenetics

    Molecular Brain 5:36.

    https://doi.org/10.1186/1756-6606-5-36

    • PubMed
    • Google Scholar
30. 1. Ji G
    2. Neugebauer V

    (2014) CB1 augments mGluR5 function in medial prefrontal cortical neurons to inhibit amygdala hyperactivity in an arthritis pain model

    The European Journal of Neuroscience 39:455–466.

    https://doi.org/10.1111/ejn.12432

    • PubMed
    • Google Scholar
31. 1. Kim Y
    2. Kim J
    3. Kang S
    4. Chang KA

    (2023) Depressive-like behaviors induced by mGluR5 reduction in 6xTg in mouse model of alzheimer’s disease

    International Journal of Molecular Sciences 24:13010.

    https://doi.org/10.3390/ijms241613010

    • Google Scholar
32. 1. Kiritoshi T
    2. Ji G
    3. Neugebauer V

    (2016) Rescue of impaired mGluR5-driven endocannabinoid signaling restores prefrontal cortical output to inhibit pain in arthritic rats

    The Journal of Neuroscience 36:837–850.

    https://doi.org/10.1523/JNEUROSCI.4047-15.2016

    • PubMed
    • Google Scholar
33. 1. Kolber BJ
    2. Montana MC
    3. Carrasquillo Y
    4. Xu J
    5. Heinemann SF
    6. Muglia LJ
    7. Gereau RW

    (2010) Activation of metabotropic glutamate receptor 5 in the amygdala modulates pain-like behavior

    The Journal of Neuroscience 30:8203–8213.

    https://doi.org/10.1523/JNEUROSCI.1216-10.2010

    • PubMed
    • Google Scholar
34. 1. Kramer RH
    2. Mourot A
    3. Adesnik H

    (2013) Optogenetic pharmacology for control of native neuronal signaling proteins

    Nature Neuroscience 16:816–823.

    https://doi.org/10.1038/nn.3424

    • PubMed
    • Google Scholar
35. 1. Landra-Willm A
    2. Karapurkar A
    3. Duveau A
    4. Chassot AA
    5. Esnault L
    6. Callejo G
    7. Bied M
    8. Häfner S
    9. Lesage F
    10. Wdziekonski B
    11. Baron A
    12. Fossat P
    13. Marsollier L
    14. Gasull X
    15. Boué-Grabot E
    16. Kienzler MA
    17. Sandoz G

    (2023) A photoswitchable inhibitor of TREK channels controls pain in wild-type intact freely moving animals

    Nature Communications 14:1160.

    https://doi.org/10.1038/s41467-023-36806-4

    • PubMed
    • Google Scholar
36. 1. Latremoliere A
    2. Woolf CJ

    (2009) Central sensitization: a generator of pain hypersensitivity by central neural plasticity

    The Journal of Pain 10:895–926.

    https://doi.org/10.1016/j.jpain.2009.06.012

    • PubMed
    • Google Scholar
37. 1. Lax NC
    2. George DC
    3. Ignatz C
    4. Kolber BJ

    (2014) The mGluR5 antagonist fenobam induces analgesic conditioned place preference in mice with spared nerve injury

    PLOS ONE 9:e103524.

    https://doi.org/10.1371/journal.pone.0103524

    • PubMed
    • Google Scholar
38. 1. Levitz J
    2. Broichhagen J
    3. Leippe P
    4. Konrad D
    5. Trauner D
    6. Isacoff EY

    (2017) Dual optical control and mechanistic insights into photoswitchable group II and III metabotropic glutamate receptors

    PNAS 114:E3546–E3554.

    https://doi.org/10.1073/pnas.1619652114

    • PubMed
    • Google Scholar
39. 1. López-Cano M
    2. Font J
    3. Aso E
    4. Sahlholm K
    5. Cabré G
    6. Giraldo J
    7. De Koninck Y
    8. Hernando J
    9. Llebaria A
    10. Fernández-Dueñas V
    11. Ciruela F

    (2023) Remote local photoactivation of morphine produces analgesia without opioid-related adverse effects

    British Journal of Pharmacology 180:958–974.

    https://doi.org/10.1111/bph.15645

    • PubMed
    • Google Scholar
40. 1. Ma X
    2. Johnson DA
    3. He XJ
    4. Layden AE
    5. McClain SP
    6. Yung JC
    7. Rizzo A
    8. Bonaventura J
    9. Banghart MR

    (2023) In vivo photopharmacology with a caged mu opioid receptor agonist drives rapid changes in behavior

    Nature Methods 20:682–685.

    https://doi.org/10.1038/s41592-023-01819-w

    • PubMed
    • Google Scholar
41. 1. Matera C
    2. Bregestovski P

    (2022) Light-controlled modulation and analysis of neuronal functions

    International Journal of Molecular Sciences 23:12921.

    https://doi.org/10.3390/ijms232112921

    • PubMed
    • Google Scholar
42. 1. Mazzitelli M
    2. Presto P
    3. Antenucci N
    4. Meltan S
    5. Neugebauer V

    (2022) Recent advances in the modulation of pain by the metabotropic glutamate receptors

    Cells 11:2608.

    https://doi.org/10.3390/cells11162608

    • PubMed
    • Google Scholar
43. Book

    1. Neugebauer V

    (2020) Amygdala physiology in pain

    In: Neugebauer V, editors. Handbook of behavioral neuroscience. Science Direct. pp. 101–113.

    https://doi.org/10.1016/b978-0-12-815134-1.00004-0

    • Google Scholar
44. 1. Neugebauer V
    2. Presto P
    3. Yakhnitsa V
    4. Antenucci N
    5. Mendoza B
    6. Ji G

    (2023) Pain-related cortico-limbic plasticity and opioid signaling

    Neuropharmacology 231:109510.

    https://doi.org/10.1016/j.neuropharm.2023.109510

    • PubMed
    • Google Scholar
45. 1. Nicoletti F
    2. Bockaert J
    3. Collingridge GL
    4. Conn PJ
    5. Ferraguti F
    6. Schoepp DD
    7. Wroblewski JT
    8. Pin JP

    (2011) Metabotropic glutamate receptors: from the workbench to the bedside

    Neuropharmacology 60:1017–1041.

    https://doi.org/10.1016/j.neuropharm.2010.10.022

    • PubMed
    • Google Scholar
46. 1. Nicoletti F
    2. Bruno V
    3. Ngomba RT
    4. Gradini R
    5. Battaglia G

    (2015) Metabotropic glutamate receptors as drug targets: what’s new?

    Current Opinion in Pharmacology 20:89–94.

    https://doi.org/10.1016/j.coph.2014.12.002

    • PubMed
    • Google Scholar
47. 1. Notartomaso S
    2. Scarselli P
    3. Di Pietro P
    4. Battaglia G
    5. Llebaria A
    6. Ciruela F
    7. Nicoletti F

    (2018) Mechanical allodynia assessment in a murine neuropathic pain model

    Bio-Protocol 8:e2671.

    https://doi.org/10.21769/BioProtoc.2671

    • PubMed
    • Google Scholar
48. 1. Notartomaso S
    2. Antenucci N
    3. Liberatore F
    4. Mascio G
    5. Boccadamo Pompili SV
    6. Font J
    7. Scioli M
    8. Luongo L
    9. Arcella A
    10. Gradini R
    11. Llebaria A
    12. Nicoletti F

    (2022) Light-induced activation of a specific type-5 metabotropic glutamate receptor antagonist in the ventrobasal thalamus causes analgesia in a mouse model of breakthrough cancer pain

    International Journal of Molecular Sciences 23:8018.

    https://doi.org/10.3390/ijms23148018

    • PubMed
    • Google Scholar
49. 1. Palazzo E
    2. Marabese I
    3. de Novellis V
    4. Rossi F
    5. Maione S

    (2014) Supraspinal metabotropic glutamate receptors: a target for pain relief and beyond

    The European Journal of Neuroscience 39:444–454.

    https://doi.org/10.1111/ejn.12398

    • PubMed
    • Google Scholar
50. 1. Paoletti P
    2. Ellis-Davies GCR
    3. Mourot A

    (2019) Optical control of neuronal ion channels and receptors

    Nature Reviews. Neuroscience 20:514–532.

    https://doi.org/10.1038/s41583-019-0197-2

    • PubMed
    • Google Scholar
51. Book

    1. Paxinos G
    2. Franklin KB

    (2008)

    The Coronal Plates and Diagrams

    Academic Press.

    • Google Scholar
52. 1. Pereira V
    2. Arias JA
    3. Llebaria A
    4. Goudet C

    (2023) Photopharmacological manipulation of amygdala metabotropic glutamate receptor mGlu4 alleviates neuropathic pain

    Pharmacological Research 187:106602.

    https://doi.org/10.1016/j.phrs.2022.106602

    • PubMed
    • Google Scholar
53. 1. Pittolo S
    2. Gómez-Santacana X
    3. Eckelt K
    4. Rovira X
    5. Dalton J
    6. Goudet C
    7. Pin J-P
    8. Llobet A
    9. Giraldo J
    10. Llebaria A
    11. Gorostiza P

    (2014) An allosteric modulator to control endogenous G protein-coupled receptors with light

    Nature Chemical Biology 10:813–815.

    https://doi.org/10.1038/nchembio.1612

    • PubMed
    • Google Scholar
54. 1. Ren W
    2. Neugebauer V

    (2010) Pain-related increase of excitatory transmission and decrease of inhibitory transmission in the central nucleus of the amygdala are mediated by mGluR1

    Molecular Pain 6:93.

    https://doi.org/10.1186/1744-8069-6-93

    • PubMed
    • Google Scholar
55. 1. Ren W
    2. Kiritoshi T
    3. Grégoire S
    4. Ji G
    5. Guerrini R
    6. Calo G
    7. Neugebauer V

    (2013) Neuropeptide S: a novel regulator of pain-related amygdala plasticity and behaviors

    Journal of Neurophysiology 110:1765–1781.

    https://doi.org/10.1152/jn.00874.2012

    • PubMed
    • Google Scholar
56. 1. Ricart-Ortega M
    2. Berizzi AE
    3. Pereira V
    4. Malhaire F
    5. Catena J
    6. Font J
    7. Gómez-Santacana X
    8. Muñoz L
    9. Zussy C
    10. Serra C
    11. Rovira X
    12. Goudet C
    13. Llebaria A

    (2020) Mechanistic insights into light-driven allosteric control of GPCR biological activity

    ACS Pharmacology & Translational Science 3:883–895.

    https://doi.org/10.1021/acsptsci.0c00054

    • PubMed
    • Google Scholar
57. 1. Rodriguez EA
    2. Campbell RE
    3. Lin JY
    4. Lin MZ
    5. Miyawaki A
    6. Palmer AE
    7. Shu X
    8. Zhang J
    9. Tsien RY

    (2017) The growing and glowing toolbox of fluorescent and photoactive proteins

    Trends in Biochemical Sciences 42:111–129.

    https://doi.org/10.1016/j.tibs.2016.09.010

    • PubMed
    • Google Scholar
58. 1. Shallcross J
    2. Wu L
    3. Wilkinson CS
    4. Knackstedt LA
    5. Schwendt M

    (2021) Increased mGlu5 mRNA expression in BLA glutamate neurons facilitates resilience to the long-term effects of a single predator scent stress exposure

    Brain Structure & Function 226:2279–2293.

    https://doi.org/10.1007/s00429-021-02326-4

    • PubMed
    • Google Scholar
59. 1. Szobota S
    2. Isacoff EY

    (2010) Optical control of neuronal activity

    Annual Review of Biophysics 39:329–348.

    https://doi.org/10.1146/annurev.biophys.093008.131400

    • PubMed
    • Google Scholar
60. 1. Velema WA
    2. Szymanski W
    3. Feringa BL

    (2014) Photopharmacology: beyond proof of principle

    Journal of the American Chemical Society 136:2178–2191.

    https://doi.org/10.1021/ja413063e

    • PubMed
    • Google Scholar
61. 1. Wu Y
    2. Shroff H

    (2022) Multiscale fluorescence imaging of living samples

    Histochemistry and Cell Biology 158:301–323.

    https://doi.org/10.1007/s00418-022-02147-4

    • PubMed
    • Google Scholar
62. 1. Yakhnitsa V
    2. Ji G
    3. Hein M
    4. Presto P
    5. Griffin Z
    6. Ponomareva O
    7. Navratilova E
    8. Porreca F
    9. Neugebauer V

    (2022) Kappa opioid receptor blockade in the amygdala mitigates pain like-behaviors by inhibiting corticotropin releasing factor neurons in a rat model of functional pain

    Frontiers in Pharmacology 13:903978.

    https://doi.org/10.3389/fphar.2022.903978

    • PubMed
    • Google Scholar
63. 1. Zuena AR
    2. Iacovelli L
    3. Orlando R
    4. Di Menna L
    5. Casolini P
    6. Alemà GS
    7. Di Cicco G
    8. Battaglia G
    9. Nicoletti F

    (2018) In vivo non-radioactive assessment of mGlu5 receptor-activated polyphosphoinositide hydrolysis in response to systemic administration of a positive allosteric modulator

    Frontiers in Pharmacology 9:804.

    https://doi.org/10.3389/fphar.2018.00804

    • Google Scholar

Author details

1. Serena Notartomaso

   Mediterranean Neurological Institute, IRCCS Neuromed, Pozzilli, Italy

   Contribution

   Conceptualization, Formal analysis, Investigation, Visualization, Methodology, Writing - original draft

   Contributed equally with

   Nico Antenucci

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4374-9233

2. Nico Antenucci

   Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, United States

   Contribution

   Formal analysis, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Contributed equally with

   Serena Notartomaso

   Competing interests

   No competing interests declared

3. Mariacristina Mazzitelli

   Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, United States

   Contribution

   Formal analysis, Investigation, Visualization, Methodology, Writing - original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5122-6649

4. Xavier Rovira

   MCS - Medicinal Chemistry & Synthesis, Institute for Advanced Chemistry of Catalonia, Barcelona, Spain

   Contribution

   Resources, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9764-9927

5. Serena Boccella

   Department of Experimental Medicine, Division of Pharmacology, University of Campania “Luigi Vanvitelli”, Naples, Italy

   Contribution

   Formal analysis, Investigation, Visualization, Writing - original draft

   Competing interests

   No competing interests declared

6. Flavia Ricciardi

   Department of Experimental Medicine, Division of Pharmacology, University of Campania “Luigi Vanvitelli”, Naples, Italy

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

7. Francesca Liberatore

   Mediterranean Neurological Institute, IRCCS Neuromed, Pozzilli, Italy

   Contribution

   Formal analysis, Investigation, Visualization

   Competing interests

   No competing interests declared

8. Xavier Gomez-Santacana

   MCS - Medicinal Chemistry & Synthesis, Institute for Advanced Chemistry of Catalonia, Barcelona, Spain

   Contribution

   Resources

   Competing interests

   No competing interests declared

9. Tiziana Imbriglio

   Mediterranean Neurological Institute, IRCCS Neuromed, Pozzilli, Italy

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

10. Milena Cannella

    Mediterranean Neurological Institute, IRCCS Neuromed, Pozzilli, Italy

    Contribution

    Formal analysis, Investigation

    Competing interests

    No competing interests declared

11. Charleine Zussy

    Institute of Functional Genomics IGF, National Centre for Scientific Research CNRS, INSERM, University of Montpellier, Montpellier, France

    Contribution

    Conceptualization, Supervision, Methodology

    Competing interests

    No competing interests declared

12. Livio Luongo

    Department of Experimental Medicine, Division of Pharmacology, University of Campania “Luigi Vanvitelli”, Naples, Italy

    Contribution

    Conceptualization, Supervision, Methodology

    Competing interests

    No competing interests declared

13. Sabatino Maione

    Department of Experimental Medicine, Division of Pharmacology, University of Campania “Luigi Vanvitelli”, Naples, Italy

    Contribution

    Conceptualization, Supervision, Project administration

    Competing interests

    No competing interests declared

14. Cyril Goudet

    Institute of Functional Genomics IGF, National Centre for Scientific Research CNRS, INSERM, University of Montpellier, Montpellier, France

    Contribution

    Conceptualization, Supervision, Methodology, Writing - review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-8255-3535

15. Giuseppe Battaglia

    1. Mediterranean Neurological Institute, IRCCS Neuromed, Pozzilli, Italy
    2. Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

    Contribution

    Conceptualization, Supervision, Methodology

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-7571-3417

16. Amadeu Llebaria

    MCS - Medicinal Chemistry & Synthesis, Institute for Advanced Chemistry of Catalonia, Barcelona, Spain

    Contribution

    Conceptualization, Resources, Supervision, Methodology, Writing - review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-8200-4827

17. Ferdinando Nicoletti

    1. Mediterranean Neurological Institute, IRCCS Neuromed, Pozzilli, Italy
    2. Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

    Contribution

    Conceptualization, Resources, Supervision, Funding acquisition, Project administration, Writing - review and editing

    For correspondence

    ferdinandonicoletti@hotmail.com

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-0917-443X

18. Volker Neugebauer

    1. Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, United States
    2. Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, United States
    3. Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, United States

    Contribution

    Conceptualization, Resources, Supervision, Funding acquisition, Investigation, Methodology, Project administration, Writing - review and editing

    For correspondence

    volker.neugebauer@ttuhsc.edu

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-6158-8635

• 298

  views

• 54

  downloads

• 0

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.