Amygdala is a critical site of action for pain modulation

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Millions of people around the world are affected by pain, a multidimensional experience characterized by interactions between our emotional, cognitive, sensory and motor functions.

Because pain is a complex condition, treating it efficiently continues to pose a challenge for physicians.

Past pain research typically has focused upon the spinal cord or the peripheral areas of the nervous system located outside the spinal cord and brain.

However, a research team headed by Volker E. Neugebauer, M.D., Ph.D., at the Texas Tech University Health Sciences Center (TTUHSC) School of Medicine recently investigated how some mechanisms in the brain contribute to pain.

His study, “Amygdala group II mGluRs Mediate the Inhibitory Effects of Systemic Group II mGluR Activation on Behavior and Spinal Neurons in a Rat Model of Arthritis Pain,” was published recently by the journal Neuropharmacology. Mariacristina Mazzitelli, a TTUHSC research assistant and Ph.D. candidate, is the study’s lead author.

“Our group has been interested in understanding pain mechanisms, and our unique area of expertise is really understanding that changes in the brain contribute to the persistence, intensity and other side effects of pain,” Neugebauer said.

“It is not just a sensation that let’s you know where it hurts and how intense the pain feels. It also causes anxiety, impairs quality of life and causes depression. We’re studying the brain because all of those things reside there.”

We’re studying the brain because all of those things reside there.”

To better understand what pain-related changes may occur in the brain, and how to normalize those changes, Neugebauer’s study applied an arthritis pain model and focused on the amygdala, which are almond-shaped clusters located deep inside each of the brain’s temporal lobes.

The amygdala is part of what is known as the limbic brain, a complex arrangement of nerve cells and networks that control basic survival functions, motivations and emotions like fear and play a central role in disorders like anxiety, addiction and pain.

The study specifically looked at activating what are known as group II metabotropic glutamate receptors, or II mGluRs, within the amygdala.

There are three groups of mGluRs that serve opposing functions, and activating these receptors can trigger an excitatory response between cells, which increases pain-related activity, or they can trigger an inhibitory response between cells that decreases pain-related activity.

“The idea is that if we can activate the inhibitory receptor, we could decrease brain activity, which also would decrease pain,” Neugebauer said.

To attempt the activation of an inhibitory response, Neugebauer used a previously developed compound called LY379268.

Though not commercially available, LY379268 has been explored by industry and demonstrates the ability to decrease anxiety while producing very few relatively minor side effects.

“We wanted to see if the compound had pain-relieving effects and determine the site of action,” Neugebauer said.

“In pain research, the spinal cord has traditionally been the target for interventions because it’s more easily accessible for drug applications than the brain and it’s the first line of processing information from the body before it gets to the brain.”

In the past, Neugebauer said LY379268 and other similar compounds have been thought of as acting in the spinal cord, though the evidence is not completely clear and remains somewhat controversial.

For this study, the Neugebauer team injected the drug systemically so it could circulate and act anywhere in the body or nervous system and then observed what, if any effects it produced.

Then they blocked the II mGluR receptors in the amygdala to see if that would eliminate any analgesic, or pain-relieving effects.

To attempt the activation of an inhibitory response, Neugebauer used a previously developed compound called LY379268. Though not commercially available, LY379268 has been explored by industry and demonstrates the ability to decrease anxiety while producing very few relatively minor side effects.

“And it did actually,” Neugebauer said. “So, imagine you inject this drug systemically, you block the receptors only in the amygdala, and the analgesic, or pain-relieving effect of the drug is gone.

That means the effect of the compound has not really been through an action in the spinal cord, but through an action in the area of interest in the brain, which is the amygdala. I think that’s really a fascinating key, and it was surprising that basically the entire pain-relieving effect of the drug can be explained by an action in the brain, not in the spinal cord.

This compound does have effects on the spinal cord, but not through an action in the spinal cord. That means this brain area somehow communicates with the spinal cord and regulates spinal cord activity. Our team showed this by measuring the activity of nerve cells in the spinal cord that were inhibited by LY379268, whether it was administered systemically or injected directly into the amygdala.”

Though he and his team did not develop the LY379268 compound, Neugebauer said their study has provided rationale for exploring it further, which Mazzitelli will do as part of her dissertation.

“When it’s given systemically it works, and now we know it works in the brain,” he said.

“It produces pain-relieving effects and also relieves anxiety, so it could prove to be a very good pain medication.”

Neugebauer, also director of TTUHSC’s Garrison Institute on Aging, said because current mechanistic pain research typically studies young rather than older adult animals, his team wants to investigate whether or not managing pain for conditions like arthritis is age-dependent.

Some compounds like LY379268 may or may not work in the older population, but that can’t be known until basic research is conducted on those subjects.

“Changes can happen quickly in the nervous system, maybe even in hours, so when we look at years and decades, there could be a lot of significant changes,” he said. “Maybe some targets get lost because that part of the nervous system is just not involved any more.

It’s fascinating, but it’s also amazing how little we know about normal aging disorders like pain and arthritis. In the context of aging, there is really a big knowledge gap, so that’s a direction I think we’re going to go.”


Acute pain is an important protective function, detecting harmful stimuli and preventing body damage. However, chronic pain persists for a long time after the initial affliction, losing its role as a warning signal and must be considered as a disease per se. Patients suffering from chronic pain not only experience exacerbated responses to both painful (hyperalgesia) and non-painful stimuli (allodynia) (Sandkühler, 2009) but also frequently express emotional and cognitive impairments often resulting in anxiety and depression (McWilliams et al., 2003; Moriarty et al., 2011; Bushnell et al., 2013).

Glutamate is the main excitatory neurotransmitter in the nervous system of adult mammals. Among the neurotransmitters involved in pain transmission from the periphery to the brain, glutamate has a leading role.

Glutamate is also involved in central sensitization, which is associated with chronic pain. Glutamate action is mediated through ionotropic and metabotropic receptors. Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels involved in the fast synaptic response to glutamate. Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that are responsible for the slow neuromodulatory response to glutamate. Eight mGluRs have been identified so far.

They are named mGlu1 to mGlu8 receptors by chronological order of discovery. Later, based on their sequence homology, signalization and pharmacology, they were subdivided in three groups. Group I mGluRs (mGlu1 and 5) are canonically coupled to Gαq/11 and lead to phospholipase C (PLC) activation that promotes neuronal excitability and are mostly expressed postsynaptically. In contrast, group II (mGlu2 and 3) and group III (mGlu4, 6, 7, and 8) mGluRs are predominantly coupled to Gαi/o triggering adenylate cyclase (AC) inhibition. Group II and III mGluRs also regulate neuronal excitability and synaptic transmission through Gβγ subunits, which notably inhibit voltage-sensitive calcium channels and activate potassium channels. Both group II and group III mGluRs are mainly localized on presynaptic terminals. Both iGluRs and mGluRs (except mGlu6 receptor) are expressed all along the pain neuraxis where they shape the transmission of pain information (Figure ​(Figure1).1).

They are also involved in the induction and the maintenance of central sensitization of the pain pathway (Latremoliere and Woolf, 2009). This phenomenon is associated with hyperexcitability of the glutamatergic system which leads to the development of the main sensory symptoms observed in persons suffering from chronic pain.

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Figure 1
Distribution of mGluRs throughout important areas involved in pain. For (A-F, J-L) pictures, masks with pseudo colors were used to color scale the relative expression level of mGluR transcripts across sections (scale displayed at the bottom of the figure). For (G-I, M-P), no expression filter was applied to recolour the ISH pictures. Image credit: Allen Institute. Masked ISH images of mGlu1 (A) and mGlu5 (B) transcripts in mice coronal section, notably in Thalamus and Amygdala. CeA (central nucleus of the amygdala) is magnified in the right panels (white dotted line, drawn according to the Allen Brain Atlas). Distribution of mGlu1 (B,C) and mGlu5 (E,F) mRNA in mice midbrain and medulla sections involved in descending modulation of pain. Magnification of the periaqueductal gray (PAG) and rostro ventral medulla (RVM) areas are shown in the right panels (white dotted line, drawn according to the Allen Brain Atlas). ISH images of mGlu3 (G) transcript in mice coronal section, notably in Thalamus and Amygdala. CeA is magnified in the left panel (white dotted line). Distribution of mGlu3 (H,I) mRNA in mice midbrain and medulla. Magnification of the PAG and RVM nucleus are shown in the left panels (white dotted line). Masked ISH images of mGlu4 (J) transcript in mice coronal section, notably in Thalamus and Amygdala. CeA is magnified in the left panel (white dotted line). Distribution of mGlu4 (K,L) mRNA in mice midbrain and medulla. Magnification of the PAG and RVM nucleus are shown in the left panels (white dotted line). Images are available for mGlu1 receptor (GMR1 gene) at http://mouse.brain-map.org/experiment/show/79591723, for mGlu5 receptor (GRM5 gene) at http://mouse.brain-map.org/experiment/show/73512423, for mGlu3 receptor (GMR3 gene) at http://mouse.brain-map.org/experiment/show/539, and for mGlu4 receptor (GRM4 gene) at http://mouse.brain-map.org/experiment/show/71247631. Distribution of mGlu1 (M), mGlu5 (N), mGlu3 (O), mGlu4 (P) transcripts in mice spinal cord. Bottom panels are magnification of the dorsal horn. Images are available for mGlu1 at http://mousespinal.brain-map.org/imageseries/show.html?id=100036413, for mGlu5 receptor at http://mousespinal.brain-map.org/imageseries/show.html?id=100033614, for mGlu3 receptor at http://mousespinal.brain-map.org/imageseries/show.html?id=100039062 and for mGlu4 receptor at http://mousespinal.brain-map.org/imageseries/show.html?id=100018200.

Acting on the molecular mechanisms of glutamatergic transmission may, therefore, be a way of developing future analgesics counteracting chronic pain. However, even if iGluR selective antagonists have proven efficacious in releasing several pain states, drastically inhibiting glutamatergic transmission via iGluR blocking inevitably induces numerous side effects, notably hallucinations, ataxia and sedation (Bleakman et al., 2006).

Therefore, the strategy of pharmacological modulation of mGluRs for the treatment of pain has been favored and significant effort has been devoted to better understanding the expression, the function and the role of these receptors in pain processing.

The present review will focus on the role of mGluRs in acute and chronic pain at different levels–from the periphery to higher brain center involved in the perception and modulation of pain–and report the recent advances in the pharmacological strategy used to achieve mGluRs modulation.

Conclusion

The growing number of selective compounds for the different mGluRs has significantly improved our understanding of the specific role of each subtype in nociception. Numerous evidences tend to suggest these receptors are promising targets for the treatment of chronic pain. However, at doses proven to be analgesic, mGlu1 antagonists are associated with motor and cognitive impairment (El-Kouhen et al., 2006; Zhu et al., 2008). Similarly, deficits in motor coordination phenotype has also been observed in mGlu1 conditional knockouts in the cerebellum (Nakao et al., 2007). Although mGlu5 antagonists may have psychoactive properties (Swedberg et al., 2014), mGlu5 blockade seems to elicit less side effects than mGlu1, suggesting that targeting mGlu5 may be more promising for the development of new analgesics. Regarding group II agonists, which have proven antinociceptive effects, a major concern for the treatment of persistent pain is the development of tolerance after repeated systematic injections (Jones et al., 2005; Zammataro et al., 2011). Nevertheless, epigenetic upregulation of endogenous mGlu2 receptor expression could counteract the drawback of tolerance. Group III metabotropic receptors are of a particular interest in drug development because their targeting may also decrease affective and cognitive disorders associated with chronic pain such as anxiety, depression, or fear (Zussy et al., 2018).

Given the analgesic effects observed after targeting peripheral mGluRs, peripherally restricted molecules may have satisfying analgesic effectiveness while decreasing the central-associated side effects. Furthermore, the use of new pharmacological tools such as photoswitchable or caged ligands, which allow the spatiotemporal tuning of mGluRs, could reduce off-target effects related to the modulation of the glutamatergic system outside the pain neuraxis.


Source:
Texas Tech
Media Contacts:
Suzanna Cisneros – Texas Tech
Image Source:
The image is in the public domain.

Original Research: Closed access
“Amygdala group II mGluRs mediate the inhibitory effects of systemic group II mGluR activation on behavior and spinal neurons in a rat model of arthritis pain”. Mariacristina Mazzitelli, Volker Neugebauer.
Neuropharmacology doi:10.1016/j.neuropharm.2019.107706.

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