New understandings about how neuropathic pain occurs and how it can be turned off

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Facing an urgent need for safer and more effective therapies for those suffering from debilitating pain in the midst of an opioid crisis, Saint Louis University researchers are on a mission to find a non-narcotic off-switch for pain.

In findings published in Proceedings of the National Academy of Sciences (PNAS), Saint Louis University scientists and their colleagues report progress on this front with definitive new understandings about how neuropathic pain occurs at the cellular and molecular level and how it can be turned off in a laboratory setting.

This work lays a foundation for the development of new non-opioid pain-killing therapies.

Although distinct definitions of neuropathic pain have been used over the years, its most recent (2011) and widely accepted definition is pain caused by a lesion or disease of the somatosensory system.

The somatosensory system allows for the perception of touch, pressure, pain, temperature, position, movement and vibration.

The somatosensory nerves arise in the skin, muscles, joints and fascia and include thermoreceptors, mechanoreceptors, chemoreceptors, pruriceptors and nociceptors that send signals to the spinal cord and eventually to the brain for further processing (BOX 1); most sensory processes involve a thalamic nucleus receiving a sensory signal that is then directed to the cerebral cortex.

Lesions or diseases of the somatosensory nervous system can lead to altered and disordered transmission of sensory signals into the spinal cord and the brain; common conditions associated with neuropathic pain include postherpetic neuralgia, trigeminal neuralgia, painful radiculopathy, diabetic neuropathy, HIV infection, leprosy, amputation, peripheral nerve injury pain and stroke (in the form of central post-stroke pain) (FIG. 1).

Not all patients with peripheral neuropathy or central nervous injury develop neuropathic pain; for example, a large cohort study of patients with diabetes mellitus indicated that the overall prevalence of neuropathic pain symptoms was 21% in patients with clinical neuropathy.

However, the prevalence of neuropathic pain increased to 60% in those with severe clinical neuropathy1.

Importantly, neuropathic pain is mechanistically dissimilar to other chronic pain conditions such as inflammatory pain that occurs, for example, in rheumatoid arthritis, in which the primary cause is inflammation with altered chemical events at the site of inflammation; such pain is diagnosed and treated differently2

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The peripheral and central changes induced by nerve injury or peripheral neuropathyPreclinical animal studies have shown that damage to all sensory peripheral fibres (namely, Aβ, Aδ and C fibres; BOX 1) alters transduction and transmission due to altered ion channel function. These alterations affect spinal cord activity, leading to an excess of excitation coupled with a loss of inhibition. In the ascending afferent pathways, the sensory components of pain are via the spinothalamic pathway to the ventrobasal medial and lateral areas (1), which then project to the somatosensory cortex allowing for the location and intensity of pain to be perceived (2). The spinal cord also has spinoreticular projections and the dorsal column pathway to the cuneate nucleus and nucleus gracilis (3). Other limbic projections relay in the parabrachial nucleus (4) before contacting the hypothalamus and amygdala, where central autonomic function, fear and «anxiety are altered (5). Descending efferent pathways from the amygdala and hypothalamus (6) drive the periaqueductal grey, the locus coeruleus, A5 and A7 nuclei and the rostroventral medial medulla. These brainstem areas then project to the spinal cord through descending noradrenaline (inhibition via α2 adrenoceptors), and, in neuropathy, there is a loss of this control and increased serotonin descending excitation via 5-HT3 receptors (7). The changes induced by peripheral neuropathy on peripheral and central functions are shown. Adapted with permission from REF. 38, Mechanisms and management of diabetic painful distal symmetrical polyneuropathy, American Diabetes Association, 2013. Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association.

Box 1

Key terms

Action potential

An electrical event in which the membrane potential of a cell in the nervous system rapidly rises and falls to transmit electrical signals from cell to cell.

Allodynia

Pain caused by a normally non-painful stimulus.

Aβ fibres

Sensory nerve fibres with a thick myelin sheath, which insulates the axon of the cell and normally promotes the conduction of touch, pressure, proprioception and vibration signals (35–90 metres per second).

Aδ fibres

Sensory nerve fibres with a myelin sheath, which insulates the axon of the cell and promotes the conduction of cold, pressure and pain signals (5–30 metres per second), that produce the acute and sharp experience of pain.

C fibres

Unmyelinated pain nerve fibres that respond to warmth and a range of painful stimuli by producing a long-lasting burning sensation due to a slow conduction speed (0.5–2 metres per second).

Chemoreceptors

Receptors that transduce chemical signals.

Complex regional pain syndromes

Also known as causalgia and reflex sympathetic dystrophy, complex regional pain syndromes are conditions that are characterized by the presence of chronic, intense pain (often in one arm, leg, hand or foot) that worsens over time and spreads in the affected area. These conditions are typically accompanied by a colour or temperature change of the skin where the pain is felt.

Conditioned pain modulation

A reduction of a painful test stimulus under the influence of a conditioning stimulus.

Dynamic mechanical allodynia

A type of mechanical allodynia that occurs when pain is elicited by lightly stroking the skin.

Expectancy-induced analgesia

A reduction of pain experience due to anticipation, desire and belief of hypoalgesia or analgesia.

Hyperalgesia

A heightened experience of pain caused by a noxious stimulus.

Hypoalgesia

A decreased perception of pain caused by a noxious stimulus.

Mechanoreceptors

A sensory receptor that transduces mechanical stimulations.

Nociceptors

A peripheral nervous system receptor that is responsible for transducing and encoding painful stimuli.

Paradoxical heat sensation

An experienced sensation of heat provoked by a cold stimulus.

Provoked pain

Pain provoked by applying a stimulus.

Pruriceptors

Sensory receptors that transduce itchy sensations.

Second-order nociceptive neurons

Nociceptive neurons in the central nervous system that are activated by the Aβ, Aδ and C afferent fibres and convey sensory information from the spinal cord to other spinal circuits and the brain.

Static pain

Another kind of mechanical hyperalgesia in those with neuropathic pain when pain is provoked after gentle pressure is applied on the symptomatic area.

Temporal summation

The phenomenon in which progressive increases in pain intensity are experienced during the repetition of identical nociceptive stimuli.

Thermoreceptors

Sensory receptors that respond to changes in temperature.


Experts believe the condition affects anywhere from 15 to 30 million people in the U.S. and that treatment carries an economic burden of more than $600 billion.

Daniela Salvemini, Ph.D., professor of pharmacology and physiology and director of The Henry and Amelia Nasrallah Center for Neuroscience at Saint Louis University, says that neuropathic pain can be exceedingly difficult to treat.

“Neuropathic pain can be severe and does not always respond to treatment,” Salvemini said.

“Opioid pain killers are widely used but can cause strong side effects and carry risks of addiction and abuse. “There is an urgent need for better options for patients suffering from chronic pain.”

Salvemini has spent her career studying the mechanisms of pain, sussing out the molecular series of interactions that lead to pain in the body. Building on previous research, Salvemini and her colleagues found that a particular cellular receptor appears to be the culprit in the development of traumatic nerve injury pain in an animal model.

In response to a nerve injury, the body generates a molecule called sphingosine-1-phosphate (S1P) in the dorsal horn of the spinal cord. S1P, in turn, can activate the receptor protein sphingosine 1-phosphate receptor subtype 1 (S1PR1) on the surface of specialized nervous system support cells called astrocytes, resulting in neuroinflammation.

In fact, pain pathways appear to depend on the activation of S1PR1; conversely, blocking this signal limits or stops pain.

“For the first time, this study clearly establishes that S1P activation of S1PR1 signaling in astrocytes is required for the development and maintenance of traumatic nerve injury-induced neuropathic pain,” Salvemini said.

“Several important findings have emerged from our studies.

We unequivocally established that activation and not inhibition of S1PR1 drives and maintains neuropathic pain. Consequently, turning S1PR1 off—not on—is required to inhibit the development of neuropathic pain and to reverse it once established.”

These findings lay the groundwork to develop a new class of medications that offer pain-killing benefits without the risks and side-effects of opioids.

“It is noteworthy that drugs that inhibited S1PR1 did not lose their beneficial effects during prolonged use nor did they engage the molecular pathways opioids use, suggesting that targeting S1PR1 is unlikely to cause opioid-like abuse,” Salvemini said.

“Collectively, our results establish S1PR1 as a good target for developing new therapies, creating a new class of non-narcotic pain-killers.”

More information: Zhoumou Chen et al, Sphingosine-1-phosphate receptor 1 activation in astrocytes contributes to neuropathic pain, Proceedings of the National Academy of Sciences (2019). DOI: 10.1073/pnas.1820466116
Journal information: Proceedings of the National Academy of Sciences
Provided by Saint Louis University

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