Sensory transduction mechanisms in chronic pain

Pain normally protects us from damaging ourselves or warns us of an injury so that we protect the injured part of the body. In these cases, the pain ceases when the harmful stimulus has gone or the injury has healed. However, in some people the pain is persistent, is no longer associated with injury and has no beneficial protective effect. This chronic pain is associated with some cancers and inflammatory diseases such as arthritis, and can occur after viral infection of the nerves that normally sense pain or after nerve damage associated with diabetes. It is estimated that 300 million people in the world suffer from chronic pain. The current pain killing drugs are mostly based on aspirin or are opiates. The aspirin-like drugs have the drawbacks that they can cause stomach bleeding and are ineffective against nerve injury pain. Apart from concerns about addiction, the opiate like drugs cause sedation, severe constipation and may even stop the patient breathing. The only other types of drugs used to treat nerve injury pain ? anticonvulsant drugs ? also have pronounced undesirable side effects, such as severe dizziness. So there is a large need for new pain killing drugs.

The molecules responsible for cold and mechanical transduction in sensory neurons in normal and chronic pain conditions are poorly understood. Molecules of the transient receptor potential (TRP) channel family are strong candidates as tranducers for these modalities. We will examine the roles of candidate TRP channels in mechano- and cold-transduction in normal and chronic pain conditions. Candidate TRP channels will be expressed in heterologous mammalian cells and their physiological and pharmacological properties determined. These properties will be compared with those of native channels in isolated sensory neurons. We will also investigate the role of individual TRP channels by molecular ?knock down? with antisense oligonucleotides (ASO) or small interfering RNA (siRNA) both in vitro and in vivo. A key part of our studies will be an examination of the behavioural effects of interfering with the actions of specific TRP channels with ASO/siRNA on mechano- and cold-transduction in normal and pathophysiological conditions. In this way we will determine:
A. What ion channels mediate innocuous and noxious mechanical transduction in sensory nerves. B. What contributions the identified ion channels make to mechanical hyperalgesia and allodynia in chronic pain conditions in vivo. C. What ion channels are responsible for innocuous and noxious cold transduction and how these channels contribute to cold allodynia in chronic pain. D. How the properties of mechano-and cold-sensitive channels are regulated in chronic pain states and the possible identity of any endogenous activators.