Award details

Connexin protein expression and gap junction connectivity in sensory spinal cord: novel facilitators of neuropathic pain?

Reference	BB/F001754/1
Principal Investigator / Supervisor	Professor Anne King
Co-Investigators / Co-Supervisors
Institution	University of Leeds
Department	Institute of Membrane & Systems Biology
Funding type	Research
Value (£)	187,287
Status	Completed
Type	Research Grant
Start date	01/06/2008
End date	31/05/2010
Duration	24 months

Abstract

Complex abnormal sensory experiences including hyperpathia or allodynia characterize human neuropathic conditions - all are highly resistant to current therapies. In trying to understand maladaptive alterations in somatosensation, current models centre on transcriptional and translational alterations in phenotype of neurons or glutamatergic/peptidergic synaptic efficacy within 'pain pathways'. In this project we will explore an alternative hypothesis which states that gap junctions (GJs) and electrical synapses within spinal dorsal horn (DH) are essential contributors to the processing of sensory afferent input by organized networks of target neurons and that corruption of this contributes to the initiation/maintenance of the neuropathic state. GJs, structurally formed by connexin (Cx) proteins, permit bidirectional transfer of small molecules and, due to specialized biophysical properties, contribute to synchronization of activity across neuronal ensembles. Activation of interconnected networks of DH neurons that violates the normal topographical innervation pattern of peripheral nerves would profoundly distort perception and account for neuropathic dysthesia. To test this, we propose a program of work to a) delineate expression of Cx proteins in spinal DH using RT-PCR and immunolabelling, b) define electrophysiologically a role for GJs and Cx subtypes in electrically-coupled networks within DH that generate co-ordinate synchronous behavior and c) compare these data in spinal cord of neuropathic animals. For this, we will take advantage of new generation compounds that more selectively modify GJ coupling and transgenic mice that permit visualization of spinal Cx expression. Identification of novel neurobiological mechanisms responsible for neuropathic pain will drive a mechanism-based rational approach to treatment. With our industrial partners at Eli Lilly, our long term aim is to shift to a treatment regime that targets specific mechanisms rather than symptoms.

Summary

Pain as a perceptual experience is broadly categorized into acute physiological pain and chronic or pathological pain. The former type of pain is experienced in response to damaging stimuli and can act as an alarm system or as protection to further damage. Although it can be unpleasant when experienced, it normally has a finite duration, it disappears in parallel with injury recovery and some relief is obtained through use of a range of analgesics. Chronic pain emerges either alongside a disease states e.g. the painful inflammation that accompanies arthritis or after musculo-skeletal or nerve damage, it persists despite apparent tissue recovery and is poorly controlled even by the strongest analgesics, including morphine. In order to develop effective clinical management strategies for pathological pain, it is necessary to understand what causes the transition from physiological to pathological pain and to identify new therapeutic targets. This project will investigate a particular form of chronic pain called 'peripheral neuropathic pain' which is caused by lesions to nerves that carry sensory information from skin, muscle and visceral organs to spinal cord and brain. Neuropathic pain is often accompanied by unpleasant sensory experiences including spontaneous pain, touch-evoked pain (allodynia) and exaggerated or prolonged pain to noxious stimuli (hyperalgesia/hyperpathia). It is not entirely clear what causes these symptoms but abnormal excitability of the nervous system may be at the root of many of them. In considering this concept, much research effort has been devoted to studying changes that may occur at 'chemical synapses' where transmitters are used to pass information between neurons within a pathway. Another type of synapse, the electrical synapse, operates within the CNS and is the main focus of this project. These synapses rely on specialized structures known as gap junctions (GJs) which are formed when two closely apposed cell membranes make direct contact via a channel or 'conduit' through which small molecules can pass. Due to their specialized properties, GJs also allow electrical excitations to pass between connected cells. For many years electrical synapses were believed to provide a primitive form of communication that was restricted to invertebrates. Research over the last few years has forced a rethink and there is a growing awareness that electrical synapses support important physiological functions even in the mature mammalian CNS. A breakthrough was the identification of Connexin proteins (Cxs) that form GJ channels. A major area of research interest relevant to GJs is the phenomenon of 'rhythmicity' where neurons generate a self-sustaining pattern of behavior. GJ coupling facilitates patterned activity and in the brain it is speculated that this phenomenon is critical for cognitive processes such as perception, memory and learning. Spinal rhythmic behavior is manifest in motor (ventral horn) areas e.g. the 'central pattern generator' and walking. It is also manifest in sensory (dorsal horn, DH) regions of the spinal cord although its precise role in somatosensory processing is not yet established. The DH is functionally subdivided into regions that deal primarily with non-painful inputs (deep DH) and painful/noxious inputs (superficial DH). Sensory nerves from skin and muscle distribute to precise DH areas, forming map of the body surface. In this project, we suggest that after peripheral injury, the DH moves towards an 'open-state' where sensory excitation is propagated via GJs in a way that violates the normal pattern, this giving rise to unpleasant sensory experiences. To study this, we must profile Cx protein expression and function in normal DH and compare this to DH of animals with a neuropathic injury. If GJs and their Cx constituents are identified as contributors or facilitators of chronic pain then this should be taken into account in developing treatments

Committee	Closed Committee - Animal Sciences (AS)
Research Topics	Neuroscience and Behaviour, Pharmaceuticals
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	Industrial Partnership Award (IPA)

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