2017 Pain Research Advances

Basic to Clinical

A proposed mechanism of action for vagal afferent nerve stimulation. 

Modulation of brainstem activity and connectivity by respiratory-gated auricular vagal afferent nerve stimulation in migraine patients

Migraine is a common disorder where severe headache is accompanied by symptoms such as visual impairments or abnormalities, nausea, or abnormal hearing (i.e. ringing in ears). The exact neurological mechanisms causing migraine are not understood, however, hypersensitivity in the trigeminal sensory complex, a system of neurons that code sensations in the head and face, may play a role. A technique known as Vagal Nerve Stimulation (VNS) has shown some promise in reducing migraine, but its mechanism of action is not agreed upon. In this report, Garcia et al hypothesized that VNS works by activating a specific set of neurons, the nucleus tractus solitarii (NTS). The authors also hypothesized that stimulating the vagus nerve in synchrony with breath exhalation would fine tune VNS to activate the NTS. To test these hypotheses, the authors developed a technique where VNS was performed using a device placed in a participant’s ear and delivered VNS that was synchronized to a patient’s breathing. The technique is known as exhalatory-gated respiratory-gated auricular vagal afferent nerve stimulation (eRAVANS) and was performed in migraine sufferers and healthy controls. Using functional MRI brain imaging, the authors observed that eRAVANS specifically activated the NTS, indicating that it could potentially be used to normalize overactivity in the trigeminal sensory complex and possibly reduce migraine. Furthermore, the authors demonstrated that in migraine sufferers eRAVANS led to increases in connectivity between NTS and other brain regions involved in pain processing. Interestingly, the authors found that in migraine patients, NTS connectivity to other brain regions decreased as they approached their next migraine attack. Finally, the authors showed that eRAVANS, in migraine patients, led to increased activation of brain structures responsible for pain suppression, in response to trigeminal sensory complex stimulation. Therefore, the authors concluded that eRAVANS increased NTS connectivity in a manner that may impact migraine and found that eRAVANS was able to increase activation of brain structures that play a role in reducing pain. This work suggests that eRAVANS may have potential in treating migraine and identifies key mechanisms through which this effect may take place.

Pain Mechanisms

A novel pathway may describe the percieved intenisty of facial pain

A craniofacial-specific monosynaptic circuit enables heightened affective pain.

Painful sensations in the head and face are transmitted to the brain by neurons located in a cluster of the trigeminal ganglia (TG). This relaying of painful stimuli through the TG is different from how pain in other parts of the body is transmitted to the brain. In humans, facial pain is generally perceived as more painful and more fear inducing than pain in other parts of the body. In this report, Rodriguez et al aimed to trace the neuronal circuits that transmit painful facial stimulations to brain regions responsible for affective pain perception (i.e. fear and emotional responses to pain). The authors utilized a novel technology, that they recently developed, called Capturing Activated Neural Ensembles (CANE) to label and trace circuits involved in facial pain transmission to the Lateral Parabrachial Nucleus (PBL) – a brain region involved in the affective pain pathway. The authors found that painful stimulation in the mouse facial region activated neurons in the PBL and that these neurons in turn projected to various regions of the brain that are involved in emotions and instincts. Next, the authors used virus mediated nerve-tracing techniques to map out which nerves activated PBL neurons in response to painful facial injection. They found was that areas of the brain involved in emotion as well as the brainstem (a brain region responsible for modulatory functions) activated PBL neurons in response to painful facial stimulation.

Additionally, the authors found evidence for two pathways whereby sensory information from the TG could be transmitted to the PBL. The first pathway was previously described and involved the TG relaying information to the PBL via the spinal cord. More excitingly, the second pathway the authors found was a direct pathway from the TG to the PBL, a pathway which had not been previously described. Contrary to the findings for facial pain circuitry, painful injection in the mouse paw activated PBL neurons to a lesser extent than facial injections and did so via a pathway that relayed through the spinal cord. The authors hypothesized that the direct TG à PBL pathway would contribute to pain perception (possibly explaining the difference in pain experience between facial and body pain) and tested this hypothesis with a series of experiments where they activated and silenced the TGà PBL pathway to assess its role in pain. The authors found activating the TG à PBL pathway was aversive and possibly distressing to mice, whereas deactivating the TG à PBL pathway decreased facial nociceptive hypersensitivity in response to a painful injection.

Taken together, using a series of innovative techniques Rodriguez et al were able to tease apart the complex circuitry of facial pain sensation and identify a previously undescribed, direct pathway whereby facial sensory information is transmitted to the brain regions responsible for affective pain. The discovery of this novel pathway may have implications for clinicians treating TG related pain as current palliative neurosurgical interventions aimed at alleviating TG related pain focus only on the TG à spinal cord pathway.


Implantable light-emitting devices may help in treatment of chronic visceral pain.

Optogenetic silencing of nociceptive primary afferents reduces evoked and ongoing bladder pain.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a severe chronic pain condition resulting in a decreased quality of life and poor treatment outcomes. Patients suffer not only from bladder pain and symptoms, but also from referred pain in the lower abdomen. In animal models of IC/BPS, silencing the neurons that express Nav1.8, causes a reduction in pain. As this channel is widely expressed, in the body it is essential to silence only the neuron populations specific to the pain condition.

Optogenetics is a technique in which light-sensitive proteins are expressed in specific cell types. When exposed to certain wavelengths of light, the neurons can be activated or suppressed, allowing neurons to be controlled with a high degree of special and temporal specificity. To test whether optogenetic silencing of Nav1.8-expressing cells could reduce the discomfort of a visceral, chronic pain condition, the authors implanted IC/BPS model mice with a wireless light emitting device. Upon activation of the device, and subsequent suppression of bladder nociceptors, animals showed a significant reduction in symptoms of IC/BPS.

The field continues to develop techniques to treat human conditions through genetic tools and implantable devices.

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