Pain in infancy influences pain reactivity in later life, but how and why this occurs is poorly understood. Here we review the evidence for developmental plasticity of nociceptive pathways in animal models and discuss the peripheral and central mechanisms that underlie this plasticity. Adults who have experienced neonatal injury display increased pain and injury-induced hyperalgesia in the affected region but mild injury can also induce widespread baseline hyposensitivity across the rest of the body surface, suggesting the involvement of several underlying mechanisms, depending upon the type of early life experience. Peripheral nerve sprouting and dorsal horn central sensitization, disinhibition and neuroimmune priming are discussed in relation to the increased pain and hyperalgesia, while altered descending pain control systems driven, in part, by changes in the stress/HPA axis are discussed in relation to the widespread hypoalgesia. Finally, it is proposed that the endocannabinoid system deserves further attention in the search for mechanisms underlying injury-induced changes in pain processing in infants and children.

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Background-Neonatal surgical injury triggers developmentally-regulated long-term changes that include enhanced hyperalgesia and spinal microglial reactivity following reinjury. To further evaluate priming of response by neonatal hindpaw incision, we investigated the functional role of spinal microglial p38 mitogen-activated protein kinase following reincision in adult rodents.

Descending connections from brainstem nuclei are known to exert powerful control of spinal nociception and pain behaviours in adult mammals. Here we present evidence that descending serotonergic fibres not only inhibit nociceptive activity, but also facilitate non-noxious tactile activity in the healthy adult rat spinal dorsal horn via activation of spinal 5-HT3 receptors (5-HT3Rs). We further show that this differential serotonergic control in the adult emerges from a non-modality selective system in young rats. Serotonergic fibres exert background 5-HT3R mediated facilitation of both tactile and nociceptive spinal activity in the first three postnatal weeks. Thus, differential descending serotonergic control of spinal touch and pain processing emerges in late postnatal life to allow flexible and context-dependent brain control of somatosensation.

In young rats, below 12 days old, the rostroventral medulla exerts a tonic descending facilitation of spinal nociception, independent of ascending sensory input.

Touch sensation is primarily encoded by mechanoreceptors, sometimes called Low-Threshold Mechanoreceptors (LTMRs), with their cell bodies in the Dorsal Root Ganglia (DRG). LTMRs make up no more that 20% of all sensory neurons and exhibit great diversity in terms of molecular signature, terminal ending morphology and electrophysiological properties, mirroring the complexity of tactile experience. LTMRs are an interesting model to study the molecular cues controlling neuronal diversification in terms of both molecular specification and target-field innervation. The morphological specialization of the sensory end-organ of LTMRs exhibits striking diversity between different mechanoreceptor types and whether it occurs in the glabrous or hairy skin. Much has been learnt about transcriptional codes that define different LTMR subtypes, but the identification of molecular players that participate in their late maturation has not been extensively addressed. Here we identified the TALE homeodomain transcription factor Meis2 as a key regulator of LTMR targetfield innervation. Meis2 is specifically expressed in cutaneous LTMRs and its expression depends on target-derived signals. Meis2 gene inactivation in mouse sensory neurons precursors or early postmitotic neurons allows normal survival and specification of LTMRs. However, LTMRs lacking Meis2 show pronounced defects in end-organ innervation which was accompanied by severely impaired receptor properties and behavioral responses. These results establish Meis2 as a major transcriptional regulator controlling the orderly formation of peripheral end-organs required for touch.

Fingertip mechanoreceptors comprise sensory neuron endings together with specialized skin cells that form the end-organ. Exquisitely sensitive vibration-sensing neurons are associated with Meissner’s corpuscles and Pacinian corpuscles1. Such end-organ structures have been recognized for more than 160 years, but their exact functions have remained a matter of speculation. Here we examined the role of USH2A in touch sensation in humans and mice. The USH2A gene encodes a transmembrane protein with a very large extracellular domain. Pathogenic USH2A mutations cause Usher syndrome associated with hearing loss and visual impairment2. We show that patients with biallelic pathogenic USH2A mutations also have profound impairments in vibrotactile touch perception. Similarly, mice lacking the USH2A protein showed severe deficits in a forepaw vibrotactile discrimination task. Forepaw rapidly-adapting mechanoreceptors (RAMs) recorded from Ush2a−/− mice innervating Meissner’s corpuscles showed profound reductions in their vibration sensitivity. However, the USH2A protein was not expressed in sensory neurons, but was found in specialized terminal Schwann cells in Meissner’s corpuscles. Loss of this large extracellular tether-like protein in corpuscular end-organs innervated by RAMs was sufficient to reduce the vibration sensitivity of mechanoreceptors. Thus, USH2A expressed in corpuscular end-organs associated with vibration sensing is required to properly perceive vibration. We propose that cells within the corpuscle present a tether-like protein that may link to mechanosensitive channels in sensory endings to facilitate small amplitude vibration detection essential for the perception of fine textured surfaces.

PIEZO2 mechanosensitive channels are required for normal touch sensation. However, PIEZO2 channels are almost completely blocked at negative resting membrane potentials. We show that PIEZO2 voltage-block can be relieved by mutations at a conserved Arginine (R2756) which dramatically sensitizes the channel to mechanical stimuli. We generated Piezo2R2756H/R2756H and Piezo2R2756K/R2756K knock-in mice to ask how voltage regulates the endogenous mechanosensitivity of sensory neurons. Surprisingly, mechanosensitive currents in nociceptors, neurons that detect noxious mechanical stimuli, were substantially sensitized in Piezo2 knock-in mice, but touch receptors were largely unaffected. Piezo2 knock-in mice were hypersensitive to noxious mechanical stimuli as their nociceptors acquired properties similar to ultrasensitive touch receptors. Thus, mechanical pain sensitivity can be tuned by voltage-block of PIEZO2 channels, a channel property potentially amenable for pharmacological modulation.