Award details

Role of HCN ion channels in pain

Reference	BB/F017987/1
Principal Investigator / Supervisor	Professor Peter Anthony McNaughton
Co-Investigators / Co-Supervisors	Dr Val Saville
Institution	University of Cambridge
Department	Pharmacology
Funding type	Skills
Value (£)	72,540
Status	Completed
Type	Training Grants
Start date	01/10/2008
End date	30/09/2012
Duration	48 months

Abstract

unavailable

Summary

Pain arises when a stimulus activates a pain-specific nerve fibre (a nociceptor) by opening ion channels, causing a depolarisation (a positive change in resting membrane membrane potential) and thus triggering action potentials that propagate to the central nervous system to elicit a sensation of pain. The intensity of the pain is encoded by the frequency of action potentials elicited by the stimulus in the nociceptive nerve terminal, and it is well known that pro-inflammatory mediators, such as prostaglandin E2, enhance the sensation of pain by increasing the frequency of action potentials elicited by a painful stimulus. The rate of depolarisation between action potentials determines their frequency, and thus the pain intensity. In preliminary studies we have shown that the major modulator of this rate, and therefore of the frequency of action potentials, is the hyperpolarisation-activated inward current, Ih. Ih ion channels are made up from combinations of four different subunits, HCN1-4. We have shown that the fast-activating HCN1 subunits are expressed in large neurones sensing light touch, and we have preliminary evidence that the slower-activating HCN2 is expressed in small pain-sensitive neurones. We will use mice in which HCN subunits have been genetically deleted to find out more about the involvement of these ion channel subunits in the generation of action potentials in nociceptors and in the sensation of pain in intact animals. We will record electrical responses from neurones in cell culture, where their behaviour can more readily be investigated, using single-cell voltage clamp and patch clamp techniques. We will also study the response of wild-type and HCN knockout mice to a mild painful stimulus by measuring the time before they voluntarily withdraw from the stimulus. The following major areas will be tackled in the proposed project. (i) We will determine which HCN subunits are expressed in which types of sensory neurones, and how their behaviour is modulated by inflammatory mediators. This work will be implemented by means of whole-cell voltage clamp studies of neurons from wild-type mice and from mice in which HCN subunits 1-3 have been genetically deleted. We will study the effect on Ih of common pro-inflammatory mediators known to activate different pathways, e.g. PGE2 (cAMP/PKA pathway); bradykinin (PKC pathway) and NGF (PI3K/Src pathway). (ii) We will elucidate which intracellular signalling pathways are important in modulation of Ih. Other studies have suggested modulation of Ih by PIP2, Src, and P38MAPK apart from the well-established direct modulation by cAMP. We will ascertain the importance of these novel signalling mechanisms in nociceptors. (iii) We will use a combined in vitro and behavioural approach to study the role of HCN subunits in both inflammatory and neuropathic pain. We study mice with global and nociceptor-specific deletions of HCN1-3. We will compare the responses to painful stimuli of wild-type animals and animals in which HCN channels have been genetically deleted, before and after injection of pro-inflammatory mediators or induction of neuropathic pain using well-established models. The possibility that the HCN ion channel subunits may be important drug targets in chronic inflammatory pain is strongly suggested by our preliminary studies and deserves further investigation. There is also evidence that Ih is involved in neuropathic pain, but which subunit is important and how it enhances neuropathic pain is unknown. These studies will establish the importance of Ih in these pain states and will identify the subunit(s) responsible. These studies will advance our understanding of the role of HCN subunits in pain, and if particular subunits have crucial roles in pain the work will act as a stimulus to the development of novel analgesic drugs aimed at specifically blocking those subunits.

Committee	Not funded via Committee
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	Training Grant - Industrial Case

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