Purinergic P2X receptors (P2X) are ATP-gated ion channels that are broadly expressed in the brain, particularly in the hypothalamus. As ionic channels with high permeability to calcium, P2X play an important and active role in neural functions. The hypothalamus contains a number of small nuclei with many molecularly defined types of peptidergic neurons that affect a wide range of physiological functions, including water balance, blood pressure, metabolism, food intake, circadian rhythm, childbirth and breastfeeding, growth, stress, body temperature, and multiple behaviors. P2X are expressed in hypothalamic neurons, astrocytes, tanycytes, and microvessels. This review focuses on cell-type specific expression of P2X in the most important hypothalamic nuclei, such as the supraoptic nucleus (SON), paraventricular nucleus (PVN), suprachiasmatic nucleus (SCN), anteroventral periventricular nucleus (AVPV), anterior hypothalamic nucleus (AHN), arcuate nucleus (ARC), ventromedial hypothalamic nucleus (VMH), dorsomedial hypothalamic nucleus (DMH), tuberomammillary nucleus (TMN), and lateral hypothalamic area (LHA).> The review also notes the possible role of P2X and extracellular ATP in specific hypothalamic functions. The literature summarized here shows that purinergic signaling is involved in the control of the hypothalamic-pituitary endocrine system, the hypothalamic-neurohypophysial system, the circadian systems and nonendocrine hypothalamic functions.

• Keywords
• P2X, arcuate nucleus (ARC), extracellular ATP, hypothalamus, paraventricular nucleus (PVN), suprachiasmatic nucleus (SCN), supraoptic nucleus (SON),
• MeSH
• Adenosine Triphosphate metabolism   MeSH
• Astrocytes metabolism   MeSH
• Hypothalamus * metabolism   cytology   MeSH
• Humans MeSH
• Neurons metabolism   MeSH
• Receptors, Purinergic P2X * metabolism   genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Adenosine Triphosphate MeSH
• Receptors, Purinergic P2X * MeSH

Alterations in the excitability of dorsal root ganglion (DRG) neurons are critical in the pathogenesis of acute and chronic pain. Neurotransmitter release from the terminals of DRG neurons is regulated by cannabinoid receptor 1 (CB1) and transient receptor potential vanilloid 1 (TRPV1), both activated by anandamide (AEA). In our experiments, the AEA precursor N-arachidonoylphosphatidylethanolamine (20:4-NAPE) was used to study the modulation of nociceptive DRG neurons excitability using K+-evoked Ca2+ transients. Intrathecal administration was used to evaluate in vivo effects. Application of 20:4-NAPE at lower concentrations (10 nM - 1 µM) decreased the excitability of DRG neurons, whereas the higher (10 µM) increased it. Both effects of 20:4-NAPE were blocked by the N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) inhibitor LEI-401. Similarly, lower concentrations of externally applied AEA (1 nM - 10 nM) inhibited DRG neurons, whereas higher concentration (100 nM) did not change it. High AEA concentration (10 µM) evoked Ca2+ transients dependent on TRPV1 activation in separate experiments. Inhibition of the CB1 receptor by PF514273 (400 nM) prevented the 20:4-NAPE- and AEA-induced inhibition, whereas TRPV1 inhibition by SB366791 (1 µM) prevented the increased DRG neuron excitability. In behavioral tests, lower 20:4-NAPE concentration caused hyposensitivity, while higher evoked mechanical allodynia. Intrathecal LEI-401 prevented both in vivo effects of 20:4-NAPE. These results highlight anti- and pro-nociceptive effects of 20:4-NAPE mediated by CB1 and TRPV1 in concentration-dependent manner. Our study underscores the complexity of endocannabinoid signaling in pain transmission modulation and highlights 20:4-NAPE as a potential therapeutic target, offering new insights for developing analgesic strategies.

• Keywords
• 20:4-NAPE, Anandamide, CB1, DRG neurons, NAPE-PLD, TRPV1,
• MeSH
• Endocannabinoids pharmacology   metabolism   MeSH
• Phosphatidylethanolamines * pharmacology   MeSH
• Phospholipase D * metabolism   antagonists & inhibitors   MeSH
• TRPV Cation Channels metabolism   MeSH
• Rats MeSH
• Arachidonic Acids * pharmacology   MeSH
• Neurons * drug effects   metabolism   MeSH
• Polyunsaturated Alkamides pharmacology   MeSH
• Rats, Sprague-Dawley MeSH
• Receptor, Cannabinoid, CB1 metabolism   MeSH
• Ganglia, Spinal * drug effects   metabolism   cytology   MeSH
• Calcium metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• anandamide MeSH Browser
• Endocannabinoids MeSH
• Phosphatidylethanolamines * MeSH
• Phospholipase D * MeSH
• TRPV Cation Channels MeSH
• Arachidonic Acids * MeSH
• Polyunsaturated Alkamides MeSH
• Receptor, Cannabinoid, CB1 MeSH
• Trpv1 protein, rat MeSH Browser
• Calcium MeSH

The development of painful paclitaxel-induced peripheral neuropathy (PIPN) represents a major dose-limiting side effect of paclitaxel chemotherapy. Here we report a promising effect of duvelisib (Copiktra), a novel FDA-approved PI3Kδ/γ isoform-specific inhibitor, in preventing paclitaxel-induced pain-like behavior and pronociceptive signaling in DRGs and spinal cord dorsal horn (SCDH) in rat and mouse model of PIPN. Duvelisib blocked the development of mechanical hyperalgesia in both males and females. Moreover, duvelisib prevented paclitaxel-induced sensitization of TRPV1 receptors, and increased PI3K/Akt signaling in small-diameter DRG neurons and an increase of CD68+ cells within DRGs. Specific optogenetic stimulation of inhibitory neurons combined with patch-clamp recording revealed that duvelisib inhibited paclitaxel-induced weakening of inhibitory, mainly glycinergic control on SCDH excitatory neurons. Enhanced excitatory and reduced inhibitory neurotransmission in the SCDH following PIPN was also alleviated by duvelisib application. In summary, duvelisib showed a promising ability to prevent neuropathic pain in PIPN. The potential use of our findings in human medicine may be augmented by the fact that duvelisib is an FDA-approved drug with known side effects.SIGNIFICANCE STATEMENT We show that duvelisib, a novel FDA-approved PI3Kδ/γ isoform-specific inhibitor, prevents the development of paclitaxel-induced pain-like behavior in males and females and prevents pronociceptive signaling in DRGs and spinal cord dorsal horn in rat and mouse model of paclitaxel-induced peripheral neuropathy.

• Keywords
• PI3K, TRPV1, dorsal horn, glycine, neuropathy, pain,
• MeSH
• Pain MeSH
• Phosphatidylinositol 3-Kinases MeSH
• Antineoplastic Agents, Phytogenic * pharmacology   MeSH
• Hyperalgesia chemically induced   drug therapy   prevention & control   MeSH
• Isoquinolines MeSH
• Rats MeSH
• Mice MeSH
• Peripheral Nervous System Diseases MeSH
• Neuralgia * chemically induced   drug therapy   prevention & control   MeSH
• Paclitaxel adverse effects   MeSH
• Purines MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• duvelisib MeSH Browser
• Antineoplastic Agents, Phytogenic * MeSH
• Isoquinolines MeSH
• Paclitaxel MeSH
• Purines MeSH

In rodents, the melatonin production by the pineal gland is controlled through adrenergic signaling from the suprachiasmatic nuclei and regulation of the principal enzyme in its synthesis, arylalkylamine-N-acetyltransferase (AANAT). In the present study, we identified increased isoprenaline-induced aa-nat expression and nocturnal AANAT activity in the pineal glands in response to the silencing of the signal transducer and activator of transcription 3 (STAT3) with siRNA or STAT3 inhibitors WP1066 and AZD1480. This AANAT activity enhancement in vivo did not interfere with light-induced AANAT suppression. Systemic or in vitro lipopolysaccharide (LPS) administration markedly increased Stat3 expression and STAT3 phosphorylation, but it did not significantly affect AANAT expression or activity. Simultaneous LPS administration and Stat3 silencing enhanced the aa-nat transcription and AANAT activity to a similar extent as Stat3 inhibition without LPS co-administration. Furthermore, we describe the circadian rhythmicity in Stat3 expression and the phosphorylated form of STAT3 protein in the rat pineal gland. Our data suggest that the higher nocturnal endogenous level of STAT3 in the pineal gland decelerates or hampers the process of NA-induced AANAT activation or affects the AANAT enzyme stability.

• Keywords
• STAT3, arylalkylamine-N-acetyltransferase, circadian rhythms, lipopolysaccharide, pineal gland, rat,
• Publication type
• Journal Article MeSH

The circadian clock in the suprachiasmatic nucleus (SCN) regulates daily rhythms in physiology and behaviour and is an important part of the mammalian homeostatic system. Previously, we have shown that systemic inflammatory stimulation with lipopolysaccharide (LPS) induced the daytime-dependent phosphorylation of STAT3 in the SCN. Here, we demonstrate the LPS-induced Stat3 mRNA expression in the SCN and show also the circadian rhythm in Stat3 expression in the SCN, with high levels during the day. Moreover, we examined the effects of LPS (1mg/kg), applied either during the day or the night, on the rhythm in locomotor activity of male Wistar rats. We observed that recovery of normal locomotor activity patterns took longer when the animals were injected during the night. The clock genes Per1, Per2 and Nr1d1, and phosphorylation of kinases ERK1/2 and GSK3β are sensitive to external cues and function as the molecular entry for external signals into the circadian clockwork. We also studied the immediate changes in these clock genes expressions and the phosphorylation of ERK1/2 and GSK3β in the suprachiasmatic nucleus in response to daytime or night-time inflammatory stimulation. We revealed mild and transient changes with respect to the controls. Our data stress the role of STAT3 in the circadian clock response to the LPS and provide further evidence of the interaction between the circadian clock and immune system.

• MeSH
• Circadian Rhythm drug effects   MeSH
• Rats MeSH
• Lipopolysaccharides toxicity   MeSH
• Locomotion drug effects   MeSH
• MAP Kinase Signaling System drug effects   MeSH
• Mitogen-Activated Protein Kinase 3 metabolism   MeSH
• Suprachiasmatic Nucleus metabolism   pathology   MeSH
• Rats, Wistar MeSH
• Gene Expression Regulation drug effects   MeSH
• STAT3 Transcription Factor biosynthesis   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Lipopolysaccharides MeSH
• Mitogen-Activated Protein Kinase 3 MeSH
• Stat3 protein, rat MeSH Browser
• STAT3 Transcription Factor MeSH