Activation of 5-HT5A receptor in the ventrolateral orbital cortex produces antinociceptive effects in rat models of neuropathic and inflammatory pain.

The ventrolateral orbital cortex (VLO) is identified as an integral component of the endogenous analgesic system comprising a spinal cord - thalamic nucleus submedius - VLO - periaqueductal gray (PAG) - spinal cord loop. The present study investigates the effects of 5-HT5A receptor activation in the VLO on allodynia induced by spared nerve injury and formalin-evoked flinching behavior and spinal c-Fos expression in male SD rats, and further examines whether GABAergic modulation is involved in the effects evoked by VLO 5-HT5A receptor activation. We found an upregulation of 5-HT5A receptor expression in the VLO during neuropathic and inflammatory pain states. Microinjection of the non-selective 5-HT5A receptor agonist 5-CT into the VLO dose dependently alleviated allodynia, and flinching behavior and spinal c-Fos expression, which were blocked by the selective 5-HT5A receptor antagonist SB-699551. Moreover, application of the GABAA receptor antagonist bicuculline in the VLO augmented the analgesic effects induced by 5-CT in neuropathic and inflammatory pain states, whereas the GABAA receptor agonist muscimol attenuated these analgesic effects. Additionally, the 5-HT5A receptors were found to be colocalized with GABAergic neurons in the VLO. These results provide new evidence for the involvement of central 5-HT5A receptors in the VLO in modulation of neuropathic and inflammatory pain and support the hypothesis that activation of 5-HT5A receptors may inhibit the inhibitory effect of GABAergic interneurons on output neurons projecting to the PAG (GABAergic disinhibitory mechanisms), consequently activating the brainstem descending inhibitory system that depresses nociceptive transmission at the spinal cord level.

5-HT7 Receptor Is Involved in Electroacupuncture Inhibition of Chronic Pain in the Spinal Cord.

Knee osteoarthritis (KOA) is a common and disabling condition characterized by attacks of pain around the joints, and it is a typical disease that develops chronic pain. Previous studies have proved that 5-HT1, 5-HT2, and 5-HT3 receptors in the spinal cord are involved in electroacupuncture (EA) analgesia. The 5-HT7 receptor plays antinociceptive role in the spinal cord. However, it is unclear whether the 5-HT7 receptor is involved in EA analgesia. The 5-HT7 receptor is a stimulatory G-protein (Gs)-coupled receptor that activates adenylyl cyclase (AC) to stimulate cyclic adenosine monophosphate (cAMP) formation, which in turn activates protein kinase A (PKA). In the present study, we found that EA significantly increased the tactile threshold and the expression of the 5-HT7 receptor in the dorsal spinal cord. Intrathecal injection of 5-HT7 receptor agonist AS-19 mimicked the analgesic effect of EA, while a selective 5-HT7 receptor antagonist reversed this effect. Moreover, intrathecal injection of AC and PKA antagonists prior to EA intervention prevented its anti-allodynic effect. In addition, GABAA receptor antagonist bicuculline administered (intrathecal, i.t.) prior to EA intervention blocked the EA effect on pain hypersensitivity. Our data suggest that the spinal 5-HT7 receptor activates GABAergic neurons through the Gs-cAMP-PKA pathway and participates in EA-mediated inhibition of chronic pain in a mouse model of KOA.

Factors Affecting the Re-Endothelialization of Endothelial Progenitor Cell.

The vascular endothelium, which plays an essential role in maintaining the normal shape and function of blood vessels, is a natural barrier between the circulating blood and the vascular wall tissue. The endothelial damage can cause vascular lesions, such as atherosclerosis and restenosis. After the vascular intima injury, the body starts the endothelial repair (re-endothelialization) to inhibit the neointimal hyperplasia. Endothelial progenitor cell is the precursor of endothelial cells and plays an important role in the vascular re-endothelialization. However, re-endothelialization is inevitably affected in vivo and in vitro by factors, which can be divided into two types, namely, promotion and inhibition, and act on different links of the vascular re-endothelialization. This article reviews these factors and related mechanisms.

Role of P2X7 receptor-mediated IL-18/IL-18R signaling in morphine tolerance: multiple glial-neuronal dialogues in the rat spinal cord.

UNLABELLED: The glial function in morphine tolerance has been explored, but its mechanisms remain unclear. Our previous study has showed that microglia-expressed P2X7 receptors (P2X7R) contribute to the induction of tolerance to morphine analgesia in rats. This study further explored the potential downstream mechanisms of P2X7R underlying morphine tolerance. The results revealed that the blockade of P2X7 receptor by P2X7R antagonist or targeting small interfering RNA (siRNA) reduced tolerance to morphine analgesia in the pain behavioral test and spinal extracellular recordings in vivo and whole-cell recording of the spinal cord slice in vitro. Chronic morphine treatment induced an increase in the expression of interleukin (IL)-18 by microglia, IL-18 receptor (IL-18R) by astrocytes, and protein kinase Cγ (PKCγ) by neurons in the spinal dorsal horn, respectively, which was blocked by a P2X7R antagonist or targeting siRNA. Chronic morphine treatment also induced an increased release of D-serine from the spinal astrocytes. Further, both D-amino acid oxygenase (DAAO), a degrading enzyme of D-serine, and bisindolylmaleimide α (BIM), a PKC inhibitor, attenuated morphine tolerance. The present study demonstrated a spinal mechanism underlying morphine tolerance, in which chronic morphine triggered multiple dialogues between glial and neuronal cells in the spinal cord via a cascade involving a P2X7R-IL-18-D-serine-N-methyl-D-aspartate receptor (NMDAR)-PKCγ-mediated signaling pathway. PERSPECTIVE: The present study shows that glia-neuron interaction via a cascade (P2X7R-IL-18-D-serine-NMDAR-PKCγ) in the spinal cord plays an important role in morphine tolerance. This article may represent potential new therapeutic targets for preventing morphine analgesic tolerance in clinical management of chronic pain.

Synergetic analgesia of propentofylline and electroacupuncture by interrupting spinal glial function in rats.

Previous studies indicated that disruption of glial function in the spinal cord enhanced electroacupuncture (EA) analgesia in arthritic rats, suggesting glia is involved in processing EA analgesia. To probe into the potential value for clinical practice, the present study was to investigate the effect of propentofylline, a glia inhibitor, on EA analgesia in rats. Mechanical allodynia induced by tetanic stimulation of sciatic nerve (TSS) was used as a pain model. On day 7 after TSS, EA treatment induced a significant increase in paw withdrawal threshold to mechanical stimulation. Intrathecal or intraperitoneal injection of propentofylline relieved TSS-induced mechanical allodynia. The combination of low dosage of propentofylline and EA produced more potent anti-allodynia than propentofylline or EA alone. Immunohistochemistry exhibited that TSS-induced activation of microglia and astrocytes was inhibited significantly by propentofylline. These results indicate that propentofylline and EA induce synergetic analgesia by interrupting spinal glial function.

Neurokinin-1 receptor enhances TRPV1 activity in primary sensory neurons via PKCepsilon: a novel pathway for heat hyperalgesia.

The neuropeptide substance P (SP) is expressed in unmyelinated primary sensory neurons and represents the best known "pain" neurotransmitter. It is generally believed that SP regulates pain transmission and sensitization by acting on neurokinin-1 receptor (NK-1), which is expressed in postsynaptic dorsal horn neurons. However, the expression and role of NK-1 in primary sensory neurons are not clearly characterized. Our data showed that NK-1 was expressed in both intact and dissociated dorsal root ganglion (DRG) neurons. In particular, NK-1 was mainly coexpressed with the capsaicin receptor TRPV1 (transient receptor potential vanilloid subtype 1), a critical receptor for the generation of heat hyperalgesia. NK-1 agonist [Sar(9), Met(O2)(11)]-substance P (Sar-SP) significantly potentiated capsaicin-induced currents and increase of [Ca2+]i in dissociated DRG neurons. NK-1 antagonist blocked not only the potentiation of TRPV1 currents but also heat hyperalgesia induced by intraplantar Sar-SP. NK-1 antagonist also inhibited capsaicin-induced spontaneous pain, and this inhibition was enhanced after inflammation. To analyze intracellular cross talking of NK-1 and TRPV1, we examined downstream signal pathways of G-protein-coupled NK-1 activation. Sar-SP-induced potentiation of TRPV1 was blocked by inhibition of G-protein, PLCbeta (phospholipase C-beta), or PKC but not by inhibition of PKA (protein kinase A). In particular, PKCepsilon inhibitor completely blocked both Sar-SP-induced TRPV1 potentiation and heat hyperalgesia. Sar-SP also induced membrane translocation of PKCepsilon in a portion of small DRG neurons. These results reveal a novel mechanism of NK-1 in primary sensory neurons via a possible autocrine and paracrine action of SP. Activation of NK-1 in these neurons induces heat hyperalgesia via PKCepsilon-mediated potentiation of TRPV1.