TRPM3 regulation of chronic pain

Abstract

Chronic pain is a major problem for up to 19% of the people and with the increasing age of the population the number is likely to increase. Currently the medicines available either do not relieve the pain adequately in a large percentage of patients or have undesirable side effects such as drowsiness or stomach discomfort and ulcers. We have discovered that an ion channel protein expressed by sensory nerves and in other areas in the nervous system plays an important role in the development of persistent pain associated with either nerve injury or inflammation. This is relevant for many human painful conditions associated with arthritis, shingles, back problems and surgery. Using mice where we can selectively delete the protein from different parts of the nervous system we will find out if the important site of action is in the peripheral sensory nerves, the spinal cord or the brain. We will also find out if inhibiting the function of this protein can reverse chronic pain once it has developed which will be important property for any new medicine that could be developed from our research. We will also find out how this protein operates to control pain. This will be important for an understanding of how the protein fits in with the other processes that operate in the nervous system and will aid us in developing new treatment for pain.

Technical Summary

The treatment of chronic pain is an area of significant unmet medical need. The current treatments are associated either with low efficacy in a significant percentage of patients or with undesirable side effects. The identification of a mechanism that can be exploited to develop novel analgesic drugs would be a major advance. We have discovered that genetically modified mice lacking functional TRPM3 ion channels throughout the body have normal sensitivities to mechanical and cold stimuli but fail to develop any neuropathic pain behaviours (von Frey filament, paw pressure, hot plate or cold plate) in a nerve injury model. Furthermore Trpm3-/- mice, do not develop heat or cold hypersensitivities in an inflammatory pain model.
As TRPM3 is expressed in some sensory neurons and also in the spinal cord, we will use tissue specific deletion of TRPM3 using the Cre-Lox system to determine the important site(s) of action. We will cross LoxP flankedTRPM3 mice with tissue specific Cre expressing mice to delete TRPM3 in specific cells. The effects of Sensory neuron specific deletion (Advillin-Cre mice) will be compared with sensory and spinal cord deletion (Hoxb8-Cre mice) using behavioural measures and histochemical markers of neuronal activation (e.g. p-ERK, p-p38). The importance of TRPM3 for the maintenance of chronic pain will be determined. We will use tamoxifen-inducible Cre expression to delete TRPM3 in sensory nerves or throughout the nervous system and determine if established hypersensitivities are reversed. We will also use RNA interference, administration of inhibitory monoclonal antibodies directed against TRPM3 and small molecule TRPM3 antagonists to examine the reversal of chronic pain. One or more of these approaches could offer downstream therapeutic opportunities. We will study the possible role of TRPM3 in the relay and processing of nociceptive signals using electrophysiological approaches using sensory neurons and spinal cord slices.

Planned Impact

Chronic pain affects a large segment of the population. Although estimates vary up to 19% of the population have been reported to experience chronic pain. The efficacy of the current treatments for chronic pain is limited. In patients suffering from neuropathic pain the responder rate is in the range of 30-40% range, while only 50-60% in patients with nociceptive or inflammatory pain receive adequate pain relief. Many of the drugs used are also associated with unwanted side effects that limit their use. There is therefore a significant medical need for new therapies employing either small molecules or biological reagents. The failure to develop novel effective therapies is multifactorial and includes the identification of target mechanisms that translate from pre-clinical to clinical studies. Our data with TRPM3-null mice have indicated that while they have normal sensitivities to thermal and mechanical stimuli they do not develop the hypersensitivities that occur in models of neuropathic and inflammatory pain. This makes TRPM3 an exciting potential target for drug discovery. Our studies to identify the roles of TRPM3 in the development and maintenance of chronic pain, including the important sites of action will therefore have immediate impact on drug discovery. Pharmaceutical and biotech companies will therefore be potential beneficaries of the research. The group at King's will also initiate activities to identify drug-like compounds that can be patent protected. The PI is well placed to exploit such opportunities as he was previously Head of the Chronic Pain Research Unit for a leading pharmaceutical company (Novartis). The development of an effective analgesic drug that operated via TRPM3 would have benefits for a large patient group. The research therefore has the potential to contribute to both the health and wealth of the nation and to enhance the quality of life.
The timescale for the impact will vary. For pharmaceutical companies the impact could occur in the short term with the initiation of drug discovery programs. The benefit for patients will depend on the successful development of a drug and would occur with a lag of about 8-10 years.

Publications

10 25 50
 
Description Project Grant
Amount £239,209 (GBP)
Funding ID 21543 
Organisation Versus Arthritis 
Start 09/2017 
End 08/2020
 
Description Advillin Cre mice 
Organisation University College London
Department Wolfson Institute for Biomedical Research
Country United Kingdom 
Sector Academic/University 
PI Contribution Investigation of the role of the ion channel TRPM3 to the development and maintenance of chronic pain
Collaborator Contribution Provision of genetically modified mice
Impact None yet
Start Year 2014
 
Description TRPM3 mice 
Organisation Saarland University
Country Germany 
Sector Academic/University 
PI Contribution Investigation of role of the ion channel TRPM3 to the development and maintenance of chronic pain
Collaborator Contribution Provision of genetically modified mice
Impact None yet
Start Year 2013