[Neuropathic pain decoded by microglial heterogeneity].

Lesion or diseases affecting the somatosensory system causes neuropathic pain, a debilitating chronic pain condition. Previous studies using its experimental models have demonstrated the critical contribution of microglia to the development of neuropathic pain. Upon sensing nerve damage, spinal cord microglia alter their morphology, gene expression and function, which lead to an increase in the excitability of pain-transmission neural pathway, causing the pain onset.

Microglial diversity in neuropathic pain.

Microglia play pivotal roles in controlling CNS functions in diverse physiological and pathological contexts, including neuropathic pain, a chronic pain condition caused by lesions or diseases of the somatosensory nervous system. In this review article, we summarize evidence primarily from basic research on the role of microglia in the development and remission of neuropathic pain. The identification of a subset of microglia that emerged after pain development and that was necessary for remission of neuropathic pain highlights the highly divergent and dynamic nature of microglia in the course of neuropathic pain.

A spinal microglia population involved in remitting and relapsing neuropathic pain.

Neuropathic pain is often caused by injury and diseases that affect the somatosensory system. Although pain development has been well studied, pain recovery mechanisms remain largely unknown. Here, we found that CD11c-expressing spinal microglia appear after the development of behavioral pain hypersensitivity following nerve injury.

Improvement of the affinity of an anti-rat P2X4 receptor antibody by introducing electrostatic interactions.

We have recently developed a mouse monoclonal antibody (12-10H) binding to the head domain region in rat P2X4 receptor (rP2X4R, which is crucial for the pathogenesis of neuropathic pain) expressed on the cell with the highest binding affinity (K = 20 nM). However, the 12-10H antibody failed to detect endogenously expressed P2X4Rs in microglia isolated from the spinal cord of rats whose spinal nerves were injured. Then, we prepared R5 mutant, in which five arginine residues were introduced into variable regions except for the "hot spot" in the 12-10H antibody to increase electrostatic interactions with the head domain, an anionic region, in rP2X4R.

Role of microglia and P2X4 receptors in chronic pain.

Pain plays an indispensable role as an alarm system to protect us from dangers or injuries. However, neuropathic pain, a debilitating pain condition caused by damage to the nervous system, persists for a long period even in the absence of dangerous stimuli or after injuries have healed. In this condition, pain becomes a disease itself rather than the alarm system and is often resistant to currently available medications.

Spinal astrocytes in superficial laminae gate brainstem descending control of mechanosensory hypersensitivity.

Astrocytes are critical regulators of CNS function and are proposed to be heterogeneous in the developing brain and spinal cord. Here we identify a population of astrocytes located in the superficial laminae of the spinal dorsal horn (SDH) in adults that is genetically defined by Hes5. In vivo imaging revealed that noxious stimulation by intraplantar capsaicin injection activated Hes5 SDH astrocytes via α-adrenoceptors (α-ARs) through descending noradrenergic signaling from the locus coeruleus.

Astrocytic STAT3 activation and chronic itch require IPR1/TRPC-dependent Ca signals in mice.

Background: Chronic itch is a debilitating symptom of inflammatory skin diseases, but the underlying mechanism is poorly understood. We have recently demonstrated that astrocytes in the spinal dorsal horn become reactive in models of atopic and contact dermatitis via activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) and critically contribute to chronic itch. In general, STAT3 is transiently activated; however, STAT3 activation in reactive astrocytes of chronic itch model mice persistently occurs via an unknown mechanism.

Mechanical pain of the lower extremity after compression of the upper spinal cord involves signal transducer and activator of transcription 3-dependent reactive astrocytes and interleukin-6.

Chronic pain is one of the main symptoms of spinal disorders such as spinal canal stenosis. A major cause of this pain is related to compression of the spinal cord, and chronic pain can develop at the level of the compressed spinal segment. However, in many patients chronic pain arises in an area that does not correspond to the compressed segment, and the underlying mechanism involved remains unknown.

Sensitization of spinal itch transmission neurons in a mouse model of chronic itch requires an astrocytic factor.

Background: Chronic itch is a highly debilitating symptom among patients with inflammatory skin diseases. Recent studies have revealed that gastrin-releasing peptide (GRP) and its receptor (gastrin-releasing peptide receptor [GRPR]) in the spinal dorsal horn (SDH) play a central role in itch transmission.

Objective: We aimed to investigate whether GRP-GRPR signaling is altered in SDH neurons in a mouse model of chronic itch and to determine the potential mechanisms underlying these alterations.

Temporal Kinetics of Microgliosis in the Spinal Dorsal Horn after Peripheral Nerve Injury in Rodents.

Neuropathic pain, a highly debilitating chronic pain following nerve damage, is a reflection of the aberrant functioning of a pathologically altered nervous system. Previous studies have implicated activated microglia in the spinal dorsal horn (SDH) as key cellular intermediaries in neuropathic pain. Microgliosis is among the dramatic cellular alterations that occur in the SDH in models of neuropathic pain established by peripheral nerve injury (PNI), but detailed characterization of SDH microgliosis has yet to be realized.

Duloxetine Inhibits Microglial P2X4 Receptor Function and Alleviates Neuropathic Pain after Peripheral Nerve Injury.

P2X4 receptors (P2X4R) are a family of ATP-gated non-selective cation channels. We previously demonstrated that activation of P2X4R in spinal microglia is crucial for neuropathic pain, a highly debilitating chronic pain condition, suggesting that P2X4R is a potential therapeutic target for treating neuropathic pain. Thus, the identification of a compound that has a potent inhibitory effect on P2X4R is an important clinical challenge.

A novel P2X4 receptor-selective antagonist produces anti-allodynic effect in a mouse model of herpetic pain.

Accumulating evidence indicates that purinergic P2X4 receptors (P2X4R: cation channels activated by extracellular ATP) expressed in spinal microglia are crucial for pathological chronic pain caused by nerve damage, suggesting a potential target for drug discovery. We identified NP-1815-PX (5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1, 2-b][1,4]diazepine-2,4(3H,5H)-dione) as a novel antagonist selective for P2X4R with high potency and selectivity compared with other P2XR subtypes. In in vivo assay for acute and chronic pain, intrathecal administration of NP-1815-PX produced an anti-allodynic effect in mice with traumatic nerve damage without affecting acute nociceptive pain and motor function (although its oral administration did not produce the effect).