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Introduction to the anatomy and physiology of pain pathways

Martin Koltzenburg
ICH, Neural Plasticity Unit, UCL , UK

Despite significant advances in our understanding of the neurobiology of nociception, pain continues to be a leading health problem and a significant area of unmet clinical need for novel analgesic drugs. Results from several recent large epidemiological surveys have consistently shown that the overall prevalence of chronic pain in the general populations is around 20% (Eriksen et al., 2003;Macfarlane et al., 2005;NFO World Group, 2003). Pain is the leading cause for absenteeism form work with nearly 500 million lost working days every year - costing the European economy at least €34 billion. Patients in chronic pain utilize the health care system twice as much as the general population and this chronification is a significant burden with an median pain duration of 7 years (NFO World Group, 2003). Approximately 10% of the population use analgesic medications on a regular basis (Eriksen et al., 2003;NFO World Group, 2003) leading to substantial direct and (because of the plethora of adverse events of these compounds) indirect costs. This is highlighted by the recent withdrawal of several coxibs and the fact that the fatality associated with non-steroidal analgesic drug use exceeds 5 per 100,000 – higher than that for asthma, cervical cancer or malignant melanoma (Singh, 1998). Thus, a better understanding of the neurobiology of pain is likely to have a significant impact on the general heath system and the development and appropriate use of analgesic drugs for the symptomatic treatment of pain.

The study of pain is not only important clinically, but is also an exciting neurobiological model system that allows the study of fundamental sensory processes from molecular mechanisms to cortical processing (Hunt and Koltzenburg, 2005). Currently, much research is directed towards understanding the cellular and molecular properties of peripheral nociceptors and spinal cord processes, the primary gateway of the pain pathway. Contemporary research has identified that nociceptive primary afferent neurons are essential for the perception of pain and this is perhaps best illustrated by individuals with a congenital lack of the nociceptors who suffer form insensitivity to pain. Nociceptors express a unique set of receptors and ion channels: (i) Transient receptor potentials (TRP) channels including the capsaicin receptor TRPV1 are major transducers for thermal stimuli. (ii) Different set of ion channels including the sodium channels Nav1.7, Nav1.8 and Nav1.9 appear to be essential for the transmission of noxious information. The importance of these ion channels is shown by the fact that gain of function mutations of Nav1.7 cause several hereditary painful conditions in humans such as erythermalgia. (iii) At the pivotal first synapse in the dorsal horn of the spinal cord transmission involving excitatory aminoacids and neuropeptides such as Substance P is controlled by a number of mechanisms and it is one site of action for the analgesic effect of opiates. In the spinal cord a dedicated set of neurons is employed to signal nociception to the brain. In primates painful somatic information travels through the spinothalamic tract whereas in rodents where direct spinothalamic projections are rather small in number, the spino-parabrachial projection neurons expressing the Substance P receptor appear to be more important.

The experience of pain is more than the detection of actual or potentially tissue damaging stimuli. Excitation of nociceptive system engages supraspinal centres that greatly influence the perception of pain. How these primary afferent through spinal neurons interact with the supraspinal centres is currently poorly understood and using novel tracing techniques we are only beginning to understand how information from subpopulations of sensory neurons is represented supraspinally (Braz et al., 2005). The important question how painful stimuli are processed supraspinally and how this affects emotions or learning and how in turn the sensation of pain is shaped by prior experience and expectancies will be the main topic of our symposium.

Finally, chronic pain is not simply the prolongation of acute pain in time. The last two decades of research has demonstrated an astonishing plasticity of the nociceptive nervous system in response to persistent painful stimuli. This plasticity is reflected by a host of changes on a transcriptional, cellular and system level.


Braz JM, Nassar MA, Wood JN, Basbaum AI (2005) Parallel "pain" pathways arise from subpopulations of primary afferent nociceptor. Neuron 47:787-793.

Eriksen J, Jensen MK, Sjogren P, Ekholm O, Rasmussen NK (2003) Epidemiology of chronic non-malignant pain in Denmark. Pain 106:221-228.

Hunt SP, Koltzenburg M (2005) The Neurobiology of Pain. Oxford : Oxford University Press.

Macfarlane GJ, Jones GT, McBeth J (2005) Epidemiology of pain. In: Wall and Melzack's Textbook of Pain (McMahon SB, Koltzenburg M, eds), pp 1199-1214. Philadelphia : Elsevier.

NFO World Group (2003) Pain in Europe .

Singh G (1998) Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am J Med 105:31S-38S.

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