Pain can be divided into two distinct categories, nociceptive and clinical. The detection of, or reaction to damaging or noxious stimuli, the phenomenon of nociception, is mediated in the periphery by highly specialized primary sensory neurons, the nociceptors. These have peripheral terminals that are activated only by high intensity mechanical, thermal and chemical stimuli. Nociceptive pain, the ‘ouch’ pain typically experienced on touching a hot object or stubbing a toe, is the readout from a protective system fundamental to maintaining bodily integrity in a potentially lethal environment. The key physiological role of this system is well illustrated by the tissue destruction produced both in the denervated (Charcot) joints and neuropathic ulcers in diabetic patients, or in the mutilating injuries seen in patients with congenital insensitivity to pain due to a loss of nociceptor sensory neurons during development, as a result of a mutation of the TrkA receptor (Indo et al., 1996).Nociceptive pain contributes to the pain associated with the onset of acute trauma and is amenable to a variety of therapies that directly target the nociceptor neuron. These include blocking input to the spinal cord with local anesthetic nerve blockade, epidural or spinal anesthesia or reducing transmission from the nociceptor to the CNS with high dose opioids.

Clinical pain has two general manifestations, that associated with tissue injury and inflammation, inflammatory pain, and that generated as a result of damage to the nervous system, neuropathic pain. Multiple distinct, but commonly coexisting pathophysiological mechanisms are responsible for the generation of clinical pain and these typically involve the recruitment of pain in response to sensory inputs other than just nociceptors (the pain is no longer purely nociceptive). Clinical pain, is moreover, the manifestation of profound alterations in sensory processing within the peripheral and central nervous systems, neuroplasticity. Two key features of clinical pain are that the pain may present in the absence of any obvious peripheral stimulus (spontaneous pain) and that there is typically an abnormal hypersensitivity to applied innocuous and noxious stimuli. Clinical pain can arise from insults to, or changes induced anywhere along, the somatosensory neuraxis from the peripheral innervation targets (as with osteo- or rheumatoid arthritis), in inflammatory pain, along peripheral nerves (postherpetic neuralgia and diabetic neuropathy), in the spinal cord (spinal cord injury) or the brain (stroke), for neuropathic pain.