The pharmacology of pain and analgesia exhibits plasticity in different pain states in that the signalling mechnisms change following physiopathological events. Understanding this plasticity may lead to improved therapies for the two broad major types of pain, neuropathic and inflammatory pain. Cancer pain can be one or the other or a combination yet has some unique features that will be discussed here.. The peripheral mechanisms of these types of pain are very different yet within the central nervous system the signalling systems appear to be more common.
Important changes occur in peripheral nerves following tissue damage that involve production of chemical mediators that act on C-fibres to sensitize and activate nociceptors. After nerve damage that can be caused by tumour growth in a nerve or by compression the whole signalling mechanisms of nerves alter. Following nerve activation, the first step in the way the peripheral nerves talk to CNS neurones is the release of transmitter into the spinal cord. Calcium channels control both neuronal activity and transmitter release and exhibit changes in different pain states. Gabapentin may act to alter these processes.
In the spinal cord, the release of peptides and glutamate from peripheral nerves causes activation of the N-methyl-D-aspartate (NMDA) receptor for glutamate in persistent pain states which, in concert with other systems, generates spinal hypersensitivity. Manifestations of this are wind-up and LTP and these mechanisms can enhance both the pain sensation and the receptive field size of the spinal neuronhes. This is a key target and ketamine does block the NMDA receptor complex-there is potential for drugs which lack the side-effects of ketamine through sub-type selective agents. The roles of the other receptors for glutamate are less likely to be viable targets.
Blocking the generation of excitability is one approach but increasing inhibitions may also provide novel analgesics. Advances in opioid therapy are likely to come from means of administration and release rather than novel agents - it appears that the gold standard is unbeatable. However, it is becoming clear that novel approaches to pain control may arise from modern technology. For example, it is possible to kill key anatomically and pharmacologically defined spinal neurones in animals, a very different approach to the older ablative techniques. This not only produces a longlasting reduction in pain but has revealed a hitherto spinal cord - brain - spinal cord loop that involves centres of the brain important in emotional and aversive responses to pain. Changes in this pathway have been seen in animal models of cancer induced bone pain. The multitude of receptors for 5HT lends hope for future analgesic agents in pains other than headache since this loop is partly mediated by 5HT. Even if this does not lead to therapy it will improve our understanding of the key interplay between sensory and psychological events in pain processing.