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Up-regulation of P2X4 receptors in spinal microglia aft er CHAPTER 8 Central nociceptive pathways and descending modulation Maria Fitzgerald Summary Infants and children respond to noxious stimulation from birth, but these responses arise from neural activity at diff erent levels of the central nervous system. Nociceptive activity at the level of the spinal cord or brainstem can produce refl ex movements, auto- nomic and metabolic responses that may parallel pain, but cannot be equated with true pain experience. Th e key to pain experience lies in neural activation of central regions of th e brain responsible for sensory discrimination and emotional responses. Th us higher center s in the brain allow noxious events to be discriminated from innocuous ones and create a se nse of unpleasantness and threat. Laboratory and clinical studies are building up a picture of the functional connections in regions of the brain concerned with sen- sory and emotion al aspects of pain at diff erent stages of infant and child development. Th ere is also inc reasing understanding of the maturation of endogenous control systems generated by the brai n, which are likely to determine a child \200\231s ability to cope with pain. Furthermore, evidence is increasing that excess noxious stimula- tion in early life can alter the course of development of both central nociceptive pathways and descending modulation of pain. However, of great importance is not only the sensory discrimina- tive, but also the emotion al or aff ective component of pain, and the fact that it has a uniquely unpleasant and stre ssful quality and the potential to cause great suff ering. As soon as a child is old enough for self-report, researchers and clinicians attempt to score the unpleasantness as well as the intensity of pain experience in order to better understand and alleviate the pain. Th e key to the matura- tion of this complete pain experience lies in neural activation of cen tral subcortical and cortical regions of the brain and neurosci- entists aim to map the noc iceptive output from the spinal cord as it projects through ascending pathways, brainstem, and subcortical structures to the cerebral cortex and to investigate how diff erent regions of the brain concerned with sensory and emotional aspects of pain become activated at diff erent stages of infant and child development. Another key determinant of pain experience is the activation of endogenous control mechanis ms within the CNS that can modu- late nociceptive activity through the release of endogenou s opioids and a powerful system of pathways descending from the brainstem to the spinal cor d. Th ese descending and endogenous pain modula- tory pathways are themselves controlled by subcortical and cortical networks and are the route by which factors such as attention and distraction, suggestion and expectation, stress and anxiety, context and past experience, can infl uence pain experience. Understanding the neural basis of developing endogenous des cending pain control is as important as understanding ascending pain pathways, as this will infl uence a child \200\231s ability to cope with pain and the extent to which it may be m anipulated. Introduction Pain has many dimensions and is processed at multiple diff erent lev- els of t he nervous system. When tissue is injured in young individu- als, it is essential that noci ceptive pathways in the peripheral and central nervous system (CNS) are activated to stimul ate protective behavior and alert the attention of caregivers. Th us noxious stimu- lation stimulates refl ex motor responses through circuits in the spinal cord and brainstem to ens ure that the aff ected body region is pro- tected from harm. In addition, autonomic circuit s in the brainstem and hypothalamus are activated, to produce appropriate changes in the ca rdiovascular, respiratory, and endocrine systems and main- tain homeostatic control of the body. It is these reactions that form the basis of pediatric clinical pain scores that meas ure movement, facial expression, cry, and other physiological indicators. Finally, the plasticity of these CNS pain pathways in infants and children is of great clin ical importance. Th e formation of correct connections in sensory regions of the brain is h ighly dependent on an appropriate balance of sensory input from the periphery, and excessiv e noxious stimulation in childhood may alter the formation of cortical pain connections thr ough neural activity-dependent mechanisms. Importantly, it may also change the normal balan ce of descending endogenous pain control, leaving an individual less able to cope with pain in the future. CHAPTER 8 central nociceptive pathways and descending modulation 75 In this chapter, the current state of knowledge of the develop- ment of central nociceptive pathways and descending controls is reviewed. Information has been gathered from laborator y studies in animal models and clinical and experimental investigations in infants and chil dren. Th e picture is far from complete but this is a fast moving and important area of res earch. inputs and although WDR and NS cells responding to nociceptive input can be recorded in the newborn rat dorsal horn, numbers are low in the fi rst week and build up slowly (see Table 8.1). Activity in dorsal horn networks ensure that spinal projection neurons transmit information to higher centers that is already sub- stantially altered from the original aff erent noci ceptive input. Th us noxious information may have already been dampened down or amplifi ed in magnitude and duration, through local interneuronal activity and central sensitization m echanisms both of which dif- fer in young and adult animals (see Walker and Baccei, Chapter 6, this volume). It may also be modulated by descending inhibitory or excitatory infl uenc es arising in the brainstem that also change through postnatal development (see \200\230Th e development of descend- ing brainstem modulation of nociception \200\231 section). Th e developmental anatomy and physiology of central pain pathways Th e development and mat uration of neural connections in the brain are commonly mapped in the laboratory animals us ing ana- tomical, electrophysiological and behavioral techniques, and more recently, optoge netic stimulation of genetically controlled light-sensitive neurons. Knowledge gained from the laboratory can be combined with human data, from traditional autopsy studies and more r ecently, neurophysiological recording and imaging of the living human brain using structura l and functional magnetic resonance imaging (fMRI) to provide an overall picture of the mat - uration of a particular pathway. Ascending spinal nociceptive projection pathways and cortical pain processing in adults Th e cell bodies of dorsal horn projection neurons are found in superfi cial lamina I and deep er laminae VI to V and their long axons travel up the spinal cord in the contralateral spin othalamic tract (STT). Since the STT arises from WDR and NS cells, this tract does not excl usively transmit nociceptive information but also low-threshold tactile information and tem perature sense. Th e thalamus is a major sensory integration center and the informa- tion t hat thalamic neurons receive and send on to the cerebral cor- tex through thalamocortical t racts is essential for the awareness of pain. Nevertheless, it should be remembered that on ly 10% of STT axons directly terminate in the thalamus. Th us, while the clas- sic terminat ion site of STT axons in the ventral posterior nucleus (VPn) and other sensory nuclei in th e thalamus (collectively called the ventrobasal complex) are commonly emphasized, most STT fi bres also project to the brainstem reticular formation including the periaqueductal gray (PAG), the parabrachial nucleus (PBn), the locus coeruleus, and the hypothalamus (Gauriau and Bernard, 2004; Todd 2010). Changing output from the spinal dorsal horn Nociceptive information from the periphery is f i rst integrated in the dorsal horn of the spinal cord (for the body) and trigeminal nuclei (for the head and neck). Multiple sensory aff erent nerve fi bres, car- rying information from the skin, muscle, joints, deep tissues, and organs synapse onto single dorsal horn neu rons resulting in spatial and modality convergence. Receptive fi elds of single dorsal horn neu- rons are larger and more overlapping than those of primary aff erents, and multiple s ensory modalities, such as touch and pinch, are proc- essed by single \200\230wide dynamic range \200\231 (WDR) cells. However, there are also a smaller number of \200\230nocicepti ve-specifi c \200\231 (NS) cells in the dorsal horn that receive information only from noci ceptive aff erents. Th e vast majority of dorsal horn neurons are interneurons, connecting locally with other neurons in the same segment of the spinal cord, but a small percentage ( c. 5%), both WDR and NS, are \200\230projection \200\231 cells, that have long axons that travel up the spinal cord to higher cen- tres in the CNS. Th us nociceptive information is transmitted partly by so-called \200\230labeled lines \200\231 devoted solely to nocicept ion, and partly by multimodal pathways, where nociceptive information is coded by spatial a nd temporal patterns of neuronal activity.