Researchers revealed unknown mechanism for pain control involving a newly identified group of cells in the spinal cord


Researchers in Japan have revealed a previously unknown mechanism for pain control involving a newly identified group of cells in the spinal cord, offering a potential target for enhancing the therapeutic effect of drugs for chronic pain.

While neurons may be the most well-known cells of the central nervous system, an assortment of non-neuronal cells first discovered in the mid-nineteenth century also play a wide variety of important roles.

Originally named after the Greek word for glue, these glial cells are now known to be much more than glue and in fact are critical elements for regulating neuronal development and function in the central nervous system.

Among the different types of glial cells, astrocytes are the most abundant in the central nervous system, but, unlike neurons in different brain regions, researchers still have yet to develop a detailed understanding of groupings of astrocytes with distinct properties.

Now, researchers led by Makoto Tsuda, professor at Kyushu University’s Graduate School of Pharmaceutical Sciences, have discovered a unique population of spinal cord astrocytes with a role in producing pain hypersensitivity.

Found in the outer two layers of gray matter near the back of the spinal cord – a location referred to as the superficial laminae of the spinal dorsal horn – 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.

Using mice, the researchers showed that stimulating noradrenergic (NAergic) neurons – so called for their use of noradrenaline as a neurotransmitter – that carry signals from the locus coeruleus (LC) in the brain down to the spinal dorsal horn activates the astrocytes and that the astrocyte activation results in pain hypersensitivity.

These observations overturn the prevailing view that descending LC-NAergic neurons suppress pain transmission in the spinal dorsal horn.

“The discovery of this new population of astrocytes reveals a new role of descending LC-NAergic neurons in facilitating spinal pain transmission,” explains Tsuda.

Considering these findings, suppressing signaling of these astrocytes by noradrenaline may enhance the effect of drugs for chronic pain.

To initially test this, the researchers genetically engineered mice in which response of astrocytes to noradrenaline was selectively inhibited and gave them duloxetine, an analgesic drug thought to increase levels of noradrenaline in the spinal cord by preventing uptake by descending LC-NAergic neurons.

Indeed, the modified mice exhibited an enhanced easing of chronic pain by duloxetine, further supporting the researchers’ proposed role of the astrocytes.

“Although we still need more studies with different drugs, this astrocyte population appears to be a very promising target for enhancing the therapeutic potential of drugs for chronic pain,” says Tsuda.

The locus coeruleus (LC) is a main origin of noradrenergic neurons [1–3]. Noradrenaline (NA) is a key neuromodulator to play critical roles in various higher brain functions in the central nervous system (CNS) [1, 2]. In the brain, NA contributes to arousal, attention, cognition and memory [4, 5]. NA also plays roles as modulatory systems for pain sensation in the spinal dorsal horn [6–8].

Sensory transmission is under the control of endogenous modulatory systems [6, 9–12]. Spinal cord plays a crucial role in the transmission and modulation of painful information [13, 14]. It has been reported that spinal noxious sensory transmission can be modulated by descending inhibitory modulation [6, 11] and/or facilitatory modulation [12, 15, 16].

The LC is a key structure which contributes to descending modulation of painful information in the spinal cord [17–19]. The activation of LC triggers descending inhibition to the spinal cord, and produces analgesic effect by releasing NA in the spinal cord [6].

In addition to the well-known descending projection, LC sends projections to supraspinal structures including cortical areas [20, 21]. Cortical areas, including the anterior cingulate cortex (ACC) and the insular cortex (IC), play important roles in chronic pain and emotional responses [20, 22–25].

Selective activations of the ACC and/or IC by electric stimulations or optogenetic stimulation induce modulatory effects on nociception and emotion in monkey and rodents study [20, 26, 27]. Electrical stimulation or optogenetic selective activation of pyramidal neurons acutely reduces nociceptive thresholds [26, 27].

In contrast, inhibition of pyramidal neurons in the ACC reduces hypersensitivity induced in chronic inflammatory pain model [26]. A similar analgesic effect was induced by the activation of parvalbumin-expressing interneurons in the ACC [26]. These results in animals are consistent with human imaging studies that demonstrate that the ACC is a critical area for chronic pain [20, 22, 24].

In addition to pain perception, human imaging study show that the ACC is a critical cortical area for itch sensation [28, 29]. Rodent studies demonstrate that itch stimulation can activate neurons in the ACC [30, 31].

Although descending NAergic LC-spinal system has been documented [4, 5], the functions of NAergic LC-ACC projections are not investigated yet. It is unclear if such NAergic projection may also produce analgesic effects as their descending modulation to the spinal dorsal horn.

In the present study, we take advance of the optogenetic approach to investigate the selective effect of LC-ACC projection on synaptic transmissions within the ACC as well as behavioral responses. We found that ascending LC-ACC projections enhance glutamatergic synaptic transmission and neural excitability in the ACC, and facilitated behavioral responses to pain and itch sensory stimulation in mice.

Different with the well-known mechanism of NA in the spinal cord level, our work for the first time reveals the mechanism of NA in the LC-cortical ascending pathway in sensory modulation.

Noradrenergic projections from the LC to the CNS have been implicated in many key brain functions, such as attention, arousal, learning and memory [1, 2, 49, 50]. Our present studies reveal a novel function of NAergic projection from LC to ACC, an important cortical region for the regulation of sensory process [20, 22, 23, 51].

On the contrary to the well-known inhibitory effect of sensory transmission at the spinal level, NA’s effect on ACC seems to facilitate the sensory process. In the situation encounters noxious stimuli (that causes pain sensation), activation of NAergic LC-spinal pathway will reduce the amount of nociceptive inputs to the spinal cord [17–19] but enhance the nociceptive responses in the brain.

The LC sends descending NAergic projections to the spinal cord [52], which is a major inhibitory pathway and alleviates chronic pain in the spinal cord [6, 13, 14]. This inhibitory effect is mainly mediated by α2A receptors, which are located on afferent axon inputs in the superficial laminae [53], and α2C receptors, which are located on glutamatergic interneurons, in spinal dorsal horn [54].

Meanwhile, NA enhances neural excitability in GAD67 expressing interneurons in the laminae II through activation of α1 receptor [16]. One in vivo electrophysiological experiment provides direct evidence showing the inhibitory effect of NA in spinal level, in which optogenetic stimulation of the LC-spinal cord pathway facilitates inhibitory transmissions in the superficial dorsal horn neurons [8]. This inhibition is likely mediated by both reducing the excitatory nociceptive inputs and activation of local inhibitory interneurons.

Different from the well-known descending inhibition for nociception, the effect of LC-cortical ascending pathway in pain sensation is not clear yet. Recently, Hirschberg et al., show that activation of LC-prefrontal cortex (PFC) induces aversion and anxiety and exacerbated spontaneous pain in neuropathic pain rats. However, the mechanism for the LC-PFC ascending regulation is not investigated [55].

In the present study, we found that NA from LC-ACC enhanced the excitatory transmission in the ACC, through α1 and β receptors. Light and electron microscopic observation combined with Cre-dependent tracing method provided morphological evidence that the ascending NAergic projections from LC predominately terminated on the pyramidal neurons but not interneurons in the ACC.

Functionally, bath application of NA enhanced presynaptic glutamatergic synaptic transmission to and postsynaptic cellular excitability of layer II/III pyramidal neurons, through β and α1 receptors respectively. This is confirmed by optogenetic stimulation of LC-ACC projections.

Additional in vivo unit recordings confirmed that electrical stimulating of the LC or local application of NA enhanced neural activity in the ACC. Therefore, the different mechanisms between descending inhibition and ascending facilitation pathway from the LC may be due to the different types of NAergic receptors and target neurons in the spinal cord and the cortex.

An interesting role of NA in the ACC was that NA played different effects in a dose-dependent manner. Low dose of NA or low frequency optostimulation to LC-ACC fibers strongly increased the release of glutamate to layer II/III pyramidal cells in the ACC.

On the other hand, high dose of NA or high frequency optostimulation, in addition to increased glutamate release, induced inward current in recorded pyramidal cells. It’s also shown that the increased glutamate release was mediated by β receptor and the induced inward current was mediated by α1 receptor.

Using AC1 or AC8 KO mice, we confirmed that the enhanced release of glutamate was blocked in AC8 KO mice and the induced inward current was blocked in AC1 KO mice. Thus, the facilitatory effect produced by NA in ACC may be mediated by presynaptic β receptor-AC8 signaling pathway and post-synaptic α1 receptor-AC1 signaling pathway, respectively. This finding is in consistent with our previous works, in which we have confirmed that AC-cAMP signaling pathways are involved in different forms of pain in the ACC [24, 34, 56, 57].

In the present study, except for the mechanical hypersensitivity effect, we found that the scratching behavior were enhanced after activating the NAergic projection fibers. Thus, activations of AC-cAMP signaling pathway may not be limited for the regulation of nociceptive information. It is more likely that the pathway is involved with the hypersensitivity for both pain and itching-like sensory information.

It is known that the ACC plays critical roles in both pain and itch in from rodents to human [28, 30, 51]. In animal study, nociceptive stimulation at the hindpaw increases neural activity in the ACC in vivo [58]. Animal models of chronic pain enhance glutamatergic transmission within the ACC [51, 59, 60].

In addition, itch stimulation also increases glutamatergic transmissions in the ACC [30, 61]. Interestingly, activations of pyramidal neurons by optogenetic stimulations within the ACC enhance both pain and itch behaviors [26, 31]. However, it is unclear whether pain and itch information share the common pathway in the CNS under physiological and pathophysiologic conditions.

How does activation of NA from the LC in the ACC regulate pain and itch functions is not investigated before. However, according to our results, NA may modulate both pain and itch pathway within the ACC by altering glutamatergic transmissions. Further study is certainly needed for understanding the mechanism of how NA modulate these two different sensations in detail.

In sum, we find that NAergic LC-ACC projection facilitates the excitatory synaptic transmission to pyramidal cells in the ACC and enhance the itch and pain like responses in animals. This LC-ACC ascending projection may help animals or humans to enhance behavioral responses to injury, and alert themselves from dangerous situation. It may also help to form long-term memory at cortical synapses [50], which is beneficial for human or animals to gain new knowledge from potentially dangerous information.

reference link :

More information: Yuta Kohro et al, Spinal astrocytes in superficial laminae gate brainstem descending control of mechanosensory hypersensitivity, Nature Neuroscience (2020). DOI: 10.1038/s41593-020-00713-4


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