Cellular mechanisms of hyperalgesia

It has recently been discovered that a small, well defined group of neurones in spinal dorsal horn plays a pivotal role for enhanced pain sensitivity, e.g. after inflammation or nerve injury. In the proposed project we will characterise for the first time the unique properties of these neurones using modern neurophysiological approaches. Nociceptive information is transmitted synaptically from fine primary afferents to 2nd order neurones in spinal dorsal horn. This synaptic relay is subject to clinically relevant neuroplasticity. Strong nociceptive input may induce a state of central sensitisation so that weak stimuli evoke strong responses in spinal neurones. The clinical correlates of which are allodynia and hyperalgesia. Recently it was discovered that a small group of neurones in superficial spinal dorsal horn are essential for the induction of central sensitisation [Science 268 (1999) 1558- 1561]. These neurones express the NK1 receptor for substance P. Most of these neurones project to supraspinal sites including parabrachial area (spino-parabrachial neurones, SPB neurones). Up-to-now very little is known about the properties of these neurones. In this research project we will determine the neurophysiological characteristics of these cells and search for cellular features that prime these neurones for neuroplastic changes. Since rise in intracellular calcium ion concentration is a key step for many neuroplastic changes, we will investigate the routes of calcium entry into these cells and search for functional consequences of such a rise. Possible mechanisms of central sensitisation include increase in synaptic strength between nociceptive afferents and SPB neurones, increased membrane excitability, loss of inhibitory control or changes in discharge patterns. For this research endeavor we will employ an array of modern neurophysiological and imaging technologies including whole-cell patch-clamp recordings in a spinal cord-dorsal root slice preparation, fluorometric measurements of free cytosolic calcium ion concentration and UV-flash photolysis of caged calcium. We expect that this research project will provide new insights into the cellular mechanisms of central sensitisation that may eventually lead to new targets for the prevention and treatment of chronic pain.

The central nervous system has an unimaginable complexity and this is a prerequisite for the extremely high performance of the brain. It therefore appears like a miracle when under some fortunate conditions a complex function can be assigned to a well defined group of nerve cells. Chronic pain is such a complex phenomenon and likely caused by many different mechanisms. However, it now appears that a well defined group of neurons in spinal dorsal horn plays a pivotal role for abnormal sensitivity to pain following inflammation or nerve injury. In this FWF project we investigated these neurons in vitro (i.e. in a dish) and showed that subpopulations of spinal neurons have the capacity to mediate abnormal sensitivity to pain. These neurons have a well defined location in a thin layer of the spinal cord grey matter, they directly sent the pain-related information to distinct areas in the brain and they possess binding sites for a substance which is present in sensory nerve fibres for pain (substance P). Like many other neurons in the spinal cord these neurons are excited by intense stimuli, i.e. they encode pain-related information. Normally, the degree of excitation closely matches the intensity of the stimulus. However, these neurons may become sensitized so that now low stimulus intensities cause inadequate strong excitation. We found that the information transfer between sensory nerve fibres for pain and these neurons is potentiated for prolonged periods of time after strong painful stimuli. We identified the cellular pathways which mediated this long-term potentiation and found that a number of cellular receptors and enzymes co-operate in an ordered fashion. In human volunteers we identified similar forms of long-term potentiation which can be induced by well controlled experimental pain-stimuli. In patients, trauma, surgery or inflammation likely also induces long-term potentiation and may lead to abnormal pain sensations and prolonged suffering. If so, then the presently identified cellular mechanisms may provide novel targets for a more specific and more effective treatment of chronic pain.