Synaptic Mechanism May Link Pain, Anxiety in Brain

Synaptic Mechanism May Link Pain, Anxiety in Brain | Pain Research Forum

pain and anxiety are inextricably intertwined. Anxiety disorders often develop in people with chronic pain, and being anxious worsens pain. Now, research led by Min Zhuo at the University of Toronto, Canada, indicates that a novel form of synaptic plasticity in the anterior cingulate cortex (ACC) may account for anxiety associated with chronic pain

The ACC plays a critical role in chronic pain, and human studies suggest that it might be a hub for anxiety as well. In people with chronic pain, anxiety levels predict the extent of pain, and in imaging studies, people with anxiety show increased activation in the ACC. Zhuo and colleagues had previously shown that changes in synaptic strength in the ACC contribute to the genesis of neuropathic pain, through a form of long-term potentiation (LTP), in which AMPA-type glutamate receptors are increased on the postsynaptic membrane (see PRF related news story

In the new study, Zhuo and colleagues looked at a different kind of LTP, generated by increased glutamate release from presynaptic terminals onto pyramidal neurons of the ACC. Their results show that this presynaptic LTP (pre-LTP) is induced after nerve injury or inflammation, and contributes not only to pain, but also to anxiety in a mouse model of neuropathic pain.

Incoming LTP

Pre-LTP in the hippocampus involves hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels

HCN channels and currents in both pre- and postsynaptic terminals in the ACC and, importantly, in thalamic neurons that project to the ACC. Block of HCN channels in the ACC prevented pre-LTP and reversed established pre-LTP, indicating the channels are required for induction and maintenance of plasticity. That result suggests that HCN antagonists might selectively dampen pre-LTP and the behaviors it underlies.

A cause for anxiety?

To better understand the functional physiological consequences of pre-LTP, the researchers turned to animal models of pain. Acute pain did not induce pre-LTP, but in mice with chronic inflammation or nerve injury, the synaptic amplification was saturated,

The ACC is known to play a role in providing emotional context to experiences, so the authors next investigated how anxiety impacted pre-LTP. Their experiments showed that pre-LTP was induced in normal, uninjured mice by exposure to a maze designed to amp up anxiety. In mice allowed to recover from the anxiety-provoking experience, however, pre-LTP had diminished, indicating that an anxiety-producing situation can evoke transient pre-LTP. Interestingly, classical fear conditioning did not produce pre-LTP in the mice, indicating that pre-LTP in the ACC contributes to anxiety but not fear.

Studies have shown that ACC activity is heightened not only in people experiencing physical pain, but psychological pain such as divorce, the death of a loved one—basically with suffering, Zhuo said. Much like pain patients, “we know those people suffer tremendous anxiety. We think our study will really link pain of all sorts with anxiety at the level of the ACC.” If scientists could one day find a way to safely prevent pre-LTP in the ACC, perhaps by blocking HCN channels, it might alleviate these forms of anxiety as well as in chronic pain

So it seems they may have found a biological mechanism for suffering in general.  If they could find a way to dampen the amount of “suffering” a person experiences, pain and depression would be tolerable (if they don’t go away entirely once suffering is “cured”.



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