Effects of modulation of Abeta fiber afferent input on development of the nociceptive system and neuropathic pain. – DevPain

Dorsal horn (DH) neurons receive sensory information from primary afferents that innervate the skin and deeper tissues of the body, and that respond to specific types of noxious and non-noxious stimuli. Cutaneous afferents terminate in the DH according to their sensory modality: nociceptive afferents carrying acute mechanical and thermal pain terminate in superficial DH (laminae I/II) whereas low-threshold mechanoreceptors (LTMR) that transmit innocuous tactile information terminate in deeper laminae (inner II-V). This incoming information is processed by DH circuits and is transmitted to projection neurons for relay to several brain areas.
The stereotypic pattern of primary afferent projections and mature organization of DH somatosensory circuits is established during early postnatal life via, as in other sensory systems, activity-dependent plasticity. Interestingly, nociceptive circuits appear to undergo such synaptic refinement despite the rare occurrence of noxious or harmful stimuli during early life. Accordingly, postnatal tuning of nociceptive withdrawal reflexes is not affected by noxious stimulation, but is prevented by the pharmacological blockade of low-threshold mechanical inputs from the tail.
There is broad consensus that mechanisms underlying pain symptoms in inflammatory or neuropathic chronic pain patients must also operate at the level of functional reorganization of DH circuits. For instance, mechanical allodynia requires that innocuous mechanical inputs elicit a nociceptive percept. Circuits mediating touch and pain are segregated under normal physiological conditions. But there is strong evidence for pathways that link circuits mediating touch and pain: these pathways are structurally already in place, but are masked by inhibition under physiological conditions. When that inhibition is lifted, low-threshold mechanical inputs can gain access to the pain transmission circuitry of superficial DH and produce pain. However, which LTMR, Aß-, Ad- and/or C-LTMRs, is/are involved? Is LTMR activity inducing functional changes and/or only transmitting the innocuous mechanical stimulus that provoke the sensation of pain?
The study of neuronal circuits and their impacts on physiology and physiopathology has been hampered by the relative non-specificity of pharmacological methods and the difficulty in manipulating the diverse functionally-defined sub-types of neurons that exist in the nervous system, including in the dorsal root ganglia. Here, we aim to overcome these obstacles using recently-developed innovative genetic tools to specifically modify a LTMR subtype and assess the effects on both i) the development of nociceptive circuits during early life, and ii) peripheral neuropathic pain in adults. This will be obtained by both genetically ablating these LTMR sensory neurons and by modulating their activity. The effects of these modifications will be assessed by by combining the complementary expertise of the 2 partner teams using state-of-the-art electrophysiological, immunohistochemical and behavioral methods, including Ca2+-imaging, multi-photon microscopy and targeted patch-clamp intracellular recordings in newly developed ex-vivo preparations. To our knowledge, the effect of suppressing or modulating the activity of specific LTMR sub-types on the organization, development and expression of DH pain circuits has never been examined. This study will bring new fundamental insights into how spinal circuits are established during development and potentially point to new perspectives into the mechanisms underlying the pathological changes occurring in neuropathic pain.