The role of adenosine and P2Y receptors expressed by multiple cell types in pain transmission

The role of extracellular nucleotides and nucleosides as signaling molecules in cell-to-cell communication has now been clearly established. This is particularly true in the central and peripheral nervous system, where purines and pyrimidines are involved in both physiological and pathological interactions between neurons and surrounding glial cells. It can be thus foreseen that the purinergic system could represent a new potential target for the development of effective analgesics, also through the normalization of neuronal functions and the inhibition of glial cell activation. Research in the last 15 years has progressively confirmed this hypothesis, but no purinergic-based analgesics have reach the market so far; in the present review we have collected the more recent discoveries on the role of G protein-coupled P2Y nucleotide and of adenosine receptors expressed by both neurons and glial cells under painful conditions, and we have highlighted some of the challenges that must be faced to translate basic and preclinical studies to clinics

P2Y purinergic receptors: new targets for analgesic and antimigraine drugs

Millions of individuals worldwide suffer from acute and, more severely, chronic pain conditions (e.g., neuropathic pain, and migraine). The latter bear tremendous personal, familial, and social costs, since sufferers and their relatives undergo a complete turnaround of their lives with the search of relief from pain becoming their pivotal thought. Sadly, to date no effective pharmacological approaches are available which can alleviate chronic pain significantly or in the long run in all patients. The current central strategy for the development of new and effective painkillers lies in the hypothesis that cellular and/or molecular players in nociception must exists that are not targeted by "classical" analgesics, and therefore researchers have put tremendous efforts into the in-depth analysis of the pathways leading to pain development and maintenance over time. In this complex scenario, two outsiders are now taking the center stage: glial cells in sensory ganglia and in the central nervous system, thanks to their ability to communicate with neurons and to modulate their firing, and the purinergic system. Extracellular purine and pyrimidine nucleotides are involved in the physiology of virtually every body district, and their extracellular concentrations massively increase under pathological situations, suggesting that they might represent potential targets for the modulation of disease-associated symptoms, like pain. Here, we provide an overview of the present knowledge of the role of nucleotides in nociception, with a particular emphasis on G protein-coupled P2Y receptors and their involvement in the communication between first- and second-order neurons in sensory nerve pathways and surrounding glial cells

The Purinergic System and Glial Cells : Emerging Costars in Nociception

It is now well established that glial cells not only provide mechanical and trophic support to neurons but can directly contribute to neurotransmission, for example, by release and uptake of neurotransmitters and by secreting pro- and anti-inflammatory mediators. This has greatly changed our attitude towards acute and chronic disorders, paving the way for new therapeutic approaches targeting activated glial cells to indirectly modulate and/or restore neuronal functions. A deeper understanding of the molecular mechanisms and signaling pathways involved in neuron-to-glia and glia-to-glia communication that can be pharmacologically targeted is therefore a mandatory step toward the success of this new healing strategy. This holds true also in the field of pain transmission, where the key involvement of astrocytes and microglia in the central nervous system and satellite glial cells in peripheral ganglia has been clearly demonstrated, and literally hundreds of signaling molecules have been identified. Here, we shall focus on one emerging signaling system involved in the cross talk between neurons and glial cells, the purinergic system, consisting of extracellular nucleotides and nucleosides and their membrane receptors. Specifically, we shall summarize existing evidence of novel "druggable" glial purinergic targets, which could help in the development of innovative analgesic approaches to chronic pain states

Tricorynus rudepunctatus (PIC) (Coleoptera: Anobiidae): Diagnosis and damage

The objective of this research was to identify and study a species of Anobiidae that causes great damage and is a cause of concern as an urban pest in Brazil. This species has been found infesting wood, furniture, doors, books, insect collections, tea, dried fruits, handcrafts, and many other commodities. Inspections were done in houses and storehouses in the city of Curitiba, PR, Brazil in order to collect objects and materials that present signs of anobiid attack. The only species identified was Tricorynus rudepunctatus (Coleoptera: Anobiidae). There is only one reference to this species in the central region of Brazil. Another anobiid, the book pest Tricorynus herbarius has been recorded attacking books and historical documents and Tricorynus sp. attacking forest trees, but it was not recorded in our survey. Usually, the damage caused by T. rudepunctatus is mistaken with damage by termites; and when the insect is collected it is frequently misidentified as T. herbarius or as the cigarette beetle, Lasioderma serricorne or even as Stegobium paniceum, the drugstore beetle. Some morphological characters useful to identify T. rudepunctatus are: oval body about 2.7 mm long; dark brown with smooth hairs all over the body; head concealed under the pronotum; 10-segmented antenna with the three apical segments forming a 3-segmented loose club; elytra with two grooves at the posterior edge; fore femur with a transversal line on its anterior face; pro and mesotibia with two distinct striae; metasternum longitudinally carinate in the middle. Adults and larvae bore inside the materials, forming galleries and producing a coarse powder. Keywords: Anobiids, Insect identification, Morphological characters, Urban pest

Tackling chronic pain and inflammation through the purinergic system

The purinergic system is composed of purine and pyrimidine transmitters, of the enzymes that modulate the interconversion of nucleotides and nucleosides, of the membrane transporters that control their extracellular concentrations, and of the many receptor subtypes that are responsible for their cellular responses. The components of this system are ubiquitously localized in all tissues and organs, and their involvement in several physiological conditions has been clearly demonstrated. Moreover, extracellular purine and pyrimidine concentrations raise several folds under pathological conditions like tissue damage, ischemia, and inflammation, which suggest that this signaling system might contribute both to disease outcome and, possibly, to its tentative resolution. The complexity of this system has greatly impaired the clear identification of the mediators and receptors that are actually involved in a given pathology, also due to the often opposite roles played by the various receptor subtypes. Nevertheless, this knowledge is fundamental for the possible exploitation of these molecular entities as targets for the development of new pharmacological approaches. In this review, we aim at highlighting what is currently known on the role of the purinergic system in various pain conditions and during inflammatory processes. Although some confusion may arise from conflicting results, literature data clearly show that targeting specific purinergic receptors may represent an innovative approach to various pain and inflammatory conditions, and that new purine-based drugs are now very close to reach the market with these indications

Basal astrocyte and microglia activation in the central nervous system of Familial Hemiplegic Migraine Type I mice

Background Gain-of-function missense mutations in the alpha(1A) subunit of neuronal Ca(V)2.1 channels, which define Familial Hemiplegic Migraine Type 1 (FHM1), result in enhanced cortical glutamatergic transmission and a higher susceptibility to cortical spreading depolarization. It is now well established that neurons signal to surrounding glial cells, namely astrocytes and microglia, in the central nervous system, which in turn become activated and in pathological conditions can sustain neuroinflammation. We and others previously demonstrated an increased activation of pro-algogenic pathways, paralleled by augmented macrophage infiltration, in both isolated trigeminal ganglia and mixed trigeminal ganglion neuron-satellite glial cell cultures of FHM1 mutant mice. Hence, we hypothesize that astrocyte and microglia activation may occur in parallel in the central nervous system. Methods We have evaluated signs of reactive glia in brains from naive FHM1 mutant mice in comparison with wild type animals by immunohistochemistry and Western blotting. Results Here we show for the first time signs of reactive astrogliosis and microglia activation in the naive FHM1 mutant mouse brain. Conclusions Our data reinforce the involvement of glial cells in migraine, and suggest that modulating such activation may represent an innovative approach to reduce pathology