Kyushu University researchers have uncovered a previously unknown colony of astrocytes in the spinal cord involved in a new mechanism for chronic pain control, providing a promising target for enhancing the therapeutic effect of drugs for chronic pain.
Astrocytes are specialized immune cells in the brain that support and nourish neurons and their synaptic communication. These immune cells, otherwise known as glial cells are the most abundant cell in the central nervous system (CNS), where they oversee many essential functions. In short, these immune cells are crucial for maintaining the homeostasis of the brain.
It has recently come to light that astrocytes possess distinctive morphological and functional characteristics that differ within specific areas of the brain. To date, they are implicated in many brain functions, as well as numerous brain pathologies. However, unlike neurons in different brain regions, specific networks of astrocytes with distinct properties and roles remain unmapped.
Discovering new functions for astrocytes
Now, a study from researchers at Kyushu University uncovers a previously unknown population of astrocytes that play a critical role in chronic pain control. The team states their new discovery provides a potential approach for intensifying the effect of therapeutics for chronic pain. The study is published in the journal Nature Neuroscience.
Previous studies stress chronic pain is a serious public health issue with an alarming prevalence. Despite this fact, there are limited effective preventative measures and treatments for chronic pain. Normally, pain begins with a noxious signal followed by an action potential carried by pain-sensing neurons. These neurons then elicit excitatory postsynaptic potentials in the dorsal horn of the spinal cord. As a result, the signal is then carried to the cerebral cortex, where excitatory postsynaptic potentials are translated into pain.
Since the discovery of astrocyte-neuron signaling, understanding pain conduction has been convoluted. Accordingly, pain processing is no longer seen as a repetitive relay of signals from the body to the brain, but as a complex system that can be influenced by a number of different factors, including the brain’s immune cells. It has now been established that astrocytes detect neuronal activity as a result of noxious stimulation and can release neurotransmitters to control synaptic activity, and in turn, pain.
Furthermore, accumulating evidence indicates that astrocytes are critically involved in chronic pain control. For instance, it is understood that injury induces astrocytes to become either neuroprotective or neurodegenerative. Nonetheless, the exact mechanisms and classification of these astrocytes in the dorsal horn of the spinal cord are unclear. The current study identifies a unique population of astrocytes in the dorsal horn of the spinal cord of mice that produces pain hypersensitivity when activated by nerve cells called noradrenergic neurons.
A new mechanism of chronic pain identified
The present clinical trial in mice locates an unknown network of astrocytes in the outer two layers of gray matter near the back of the spinal cord, known as the superficial laminae of the spinal dorsal horn. Findings indicate the astrocytes are in a region known to carry general sensory information such as pressure, pain, and heat from around the body to the brain.
Results show stimulating noradrenergic neurons that carry signals from the locus coeruleus in the brain to the spinal dorsal horn, activate these astrocytes with the noradrenaline to cause pain hypersensitivity. Data findings show the spinal cord neurons are using the noradrenaline they produce to activate the newly discovered astrocytes to transmit, not suppress, pain. Remarkably, these observations overturn the prevailing view that noradrenergic neurons subdue pain transmission along the spinal cord to the brain.
As their study revealed a new role for noradrenergic neurons in facilitating spinal pain transmission. This led the group to posit that suppressing signaling of the noradrenaline-activated astrocytes could enhance the effect of drugs for chronic pain.
Enhancing pain controlling drugs in the spine
To test this theory mice were genetically engineered where the response of astrocytes to noradrenaline was inhibited. The engineered mice were then given duloxetine, an analgesic drug known to prevent uptake of noradrenaline by noradrenergic neurons in the spinal cord. Specifically, this drug stops noradrenergic neurons, and by extension their connected astrocytes, in the spinal cord from absorbing noradrenaline. This means the dorsal horn astrocytes are unable to be activated by noradrenaline or to transmit pain signals to the brain.
Indeed, the modified mice exhibited signs that the inhibited astrocytes had enhanced the abatement of chronic pain by duloxetine. The lab explains their findings illuminate the fact the role of noradrenergic neurons in controlling spinal pain transmission is not just limited to suppression. Additionally, this also points to this new colony of astrocytes as ‘heightening’ the effect of chronic pain treatments.
The future for pain therapeutics
The team surmises they have identified a previously unknown population of astrocytes that are a portal to pain hypersensitivity in the spinal cord. For the future, the researchers state that although more drugs need to be investigated, this glia cell population appears to be a promising target for enhancing the therapeutic action of drugs for chronic pain.
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