Gene therapy is well established as a developing mode of cancer treatment. Application of this bio-technology is proceeding in the pain world, where there are good indications that it may offer a new modality of analgesia for patients with cancer. Work has been going on in altering the genetic content of pain nerve cells in an attempt to modulate activity and response in a variety of cancer and non-cancer pain situations. The principle is to alter the contents of the nerve cell nucleus and in doing do alter the way the cell responds to stimulus. The physiology of pain is covered in the virtualcancercentre.com Symptoms/Pain document, which is accessed through any of the clinical suites (Oncology, Radiation Oncology, Haematology or Palliative Care). To expand on this: A number of processes within the cell, and, ultimately the activity of the neurone depends upon the switching on of intracellular pathways in response to an external stimulus: Painful stimulus activates nociceptor Nociceptor activates the C-fibre Electrical impulse propagates up c-fibre neurone towards spinal cord Electrical impulse reaches cell body of C-fibre (located in dorsal root ganglion) and activates intracellular pathways Gene activation then codes for cellular response
The cellular response can vary depending on a number of factors, including chronicity of stimulus. In cases of chronic stimulus, one response may be activation of NMDA receptors which subsequently leads to wind up (Explanation of the phenomenon of wind-up is given in our pain section). This gives a potential avenue for gene therapy to alter the cellular response to painful stimulus and modulate the perception of pain. If the pain neurone could be modified to prevent NMDA activation, this would prevent the rapid, opioid resistant, increase in pain seen in wind-up.
Wind up occurs with any chronic pain state when pain remains untreated or partially treated and can occur when nerve cells become damaged, such as in Post Herpetic Neuralgia (Post shingles pain). It typically occurs in neurogenic pain states such as brachial or lumbar plexopathy.
Another potential avenue is to alter the activity of opioid receptors produced by the neurone in response to pain. Opioid receptors inhibit the release of pain causing neurotransmitter from the end of the neurone. By up-regulating these receptors (i.e. making them more efficient) it is theoretically possible to make the pain neurones more sensitive to the blocking effects of opioid analgesics like morphine, fentanyl, hydromorphone, and methadone. If the upregulatory gene therapy is applied only to pain neurones, then only they will be made more sensitive. The obvious advantages of this approach is better pain relief with lower doses and as an added bonus, less unwanted side effects. Does this mean that pain nirvana is approaching? So,is it possible to apply gene effects selectively to pain neurones?
Research discussed by A/Prof D Yeomans (USA), Dr A Mannes (USA) and A/Prof Y Saitch (Japan) at the 2002 World Pain Congress in San Diego indicates that this solution may be closer than you might think. Every day, certain biological agents attack thousands of victims,targeting pain neurones and their respective ganglia specifically, causing countless misery. This is not the product of a weapon of mass terror, but a naturally occurring phenomenon ie that of the Herpes virus.
Herpes zoster has a wonderful ability to enter via the skin, invade C-fibres and migrate proximally to the dorsal root ganglion. Once established, it can produce countless years of prolonged misery. Post Herpetic Neuralgia has traditionally been difficult to treat, in part due to the chronicity of infection and the changes it induces in the nerve cell ganglion. This persistence could be turned to therapeutic advantage.
Altered herpes virus can be applied to peripheral tissue, where it is taken up by nociceptors and transported up the neurone to the dorsal root ganglion. Here the altered DNA induces the changes within the nerve cell DNA, altering the response to pain.
Other work has been carried out using adenoviruses which also persist within the central nervous system. They may well be suitable for cancer patients who require a prolonged duration of response.
There are a number of inherent problems with the introduction of infective media for therapeutic purpose, but it should be borne in mind that man has long used viral agents for his own benefit. Examples include the use of vaccines of attenuated strains for immunization. If the obvious hurdles can be overcome, this type of approach may well find its way into routine practice in the not too distant future.