In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization

Treating pain by inhibiting ATP activation of P2X3-containing receptors heralds an exciting new approach to pain management, and Afferent's program marks the vanguard in a new class of drugs poised to explore this approach to meet the significant unmet needs in pain management. P2X3 receptor subunits are expressed predominately and selectively in so-called C- and Aδ-fiber primary afferent neurons in most tissues and organ systems, including skin, joints, and hollow organs, suggesting a high degree of specificity to the pain sensing system in the human body. P2X3 antagonists block the activation of these fibers by ATP and stand to offer an alternative approach to the management of pain and discomfort. In addition, P2X3 is expressed pre-synaptically at central terminals of C-fiber afferent neurons, where ATP further sensitizes transmission of painful signals. As a result of the selectivity of the expression of P2X3, there is a lower likelihood of adverse effects in the brain, gastrointestinal, or cardiovascular tissues, effects which remain limiting factors for many existing pain therapeutics. In the periphery, ATP (the factor that triggers P2X3 receptor activation) can be released from various cells as a result of tissue inflammation, injury or stress, as well as visceral organ distension, and stimulate these local nociceptors. The P2X3 receptor rationale has aroused a formidable level of investigation producing many reports that clarify the potential role of ATP as a pain mediator, in chronic sensitized states in particular, and has piqued the interest of pharmaceutical companies. P2X receptor-mediated afferent activation has been implicated in inflammatory, visceral, and neuropathic pain states, as well as in airways hyperreactivity, migraine, itch, and cancer pain. It is well appreciated that oftentimes new mechanisms translate poorly from models into clinical efficacy and effectiveness; however, the breadth of activity seen from P2X3 inhibition in models offers a realistic chance that this novel mechanism to inhibit afferent nerve sensitization may find its place in the sun and bring some merciful relief to the torment of persistent discomfort and pain. The development philosophy at Afferent is to conduct proof of concept patient studies and best identify target patient groups that may benefit from this new intervention

Lectin binding to primary afferents of the rat trigeminal system

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Emerging Peripheral Receptor Targets for Deep-tissue Craniofacial Pain Therapies

While effective therapies are available for some types of craniofacial pain, treatments for deep-tissue craniofacial pain such as temporomandibular disorders are less efficacious. Several ion channels and receptors which are prominent in craniofacial nociceptive mechanisms have been identified on trigeminal primary afferent neurons. Many of these receptors and channels exhibit unusual distributions compared with extracranial regions. For example, expression of the ATP receptor P2X3 is strongly implicated in nociception and is more abundant on trigeminal primary afferent neurons than analogous extracranial neurons, making them potentially productive targets specifically for craniofacial pain therapies. The initial part of this review therefore focuses on P2X3 as a potential therapeutic target to treat deep-tissue craniofacial pain. In the trigeminal ganglion, P2X3 receptors are often co-expressed with the nociceptive neuropeptides CGRP and SP. Therefore, we discuss the role of CGRP and SP in deep-tissue craniofacial pain and suggest that neuropeptide antagonists, which have shown promise for the treatment of migraine, may have wider therapeutic potential, including the treatment of deep-tissue craniofacial pain. P2X3, TRPV1, and ASIC3 are often co-expressed in trigeminal neurons, implying the formation of functional complexes that allow craniofacial nociceptive neurons to respond synergistically to altered ATP and pH in pain. Future therapeutics for craniofacial pain thus might be more efficacious if targeted at combinations of P2X3, CGRP, TRPV1, and ASIC3

Co-expression of Fos immunoreactivity in protein kinase (PKCγ)-positive neurones: quantitative analysis of a brain region involved in learning

The expression of the gamma protein kinase C isoenzyme (PKCγ) and of the c-fos immediate early gene protein product Fos in the intermediate and medial hyperstriatum ventrale (IMHV) of day-old chicks was determined immunocytochemically. Previous research has shown that (a) there is a learning-related increase in the expression of Fos in the IMHV of the chick after imprinting; (b) PKCγ is expressed in neurones in most regions of the chick forebrain, including the IMHV. In the present study it was found that in imprinted chicks, 96.5% of neurones in the IMHV that expressed Fos also stained positively for PKCγ. These results raise the possibility of a functional connection between PKCγ activation and c-fos expression in neurones in general, and in particular in neurones in the IMHV that are involved in learning.