THE PATHOPHYSIOLOGY OF PAIN PERCEPTION

S.Mercadante

Anesthesia and Intensive Care Unit

Pain Relief and Palliative Care Unit

La Maddalena Cancer Center, Palermo, Italy

Mechanisms in the central nervous system that control the perception of a noxious stimulus and modulation processes have been emphasized in the gate control theory. Despite the enormous scientific impact, however, this theory did not incorporate long-term changes and dynamic features of the central nervous systems. Physiological and behavioural studies have shown that plasticity, or learning, has a relevant role. Repetitive stimulation facilitate synaptic potentiation, and environmental influences may profoundly influence the response. Perception of pain seems to be generated by a sum of sensory inputs and regions of the brain involved in affective and cognitive activities converging in a neuromatrix which produces a final output, as a result of a complex integration of a neural network.

Although no specific consensus exists on the presence of a specific histological structure acting as nociceptive receptor, special transducers on A delta and C fibres are able to detect an offending stimulus of a certain intensity. Kinins are rapidly generated after tissue injury and seem to modulate most of the events, being implicated in neurogenic inflammatory events, activating A-delta and C-fibers. Moreover, kinins can release a large number of inflammatory mediators and sensitize primary afferent neurons. Primary hyperalgesia accounts for much of the peripheral sensitisation of nociceptors. Many nociceptors are normally silent but become excitable only under pathological conditions such as inflammation.

Among the substances liberated after tissue damage, substance P and gene related peptide can be released into the periphery via the classic axon reflex. This, in turn facilitates neurogenic inflammation, inducing the release of histamine, vasodilatation, plasma extravasation with the subsequent release of other algogens and activation of inflammatory cells, as well as nitric oxide. Prostaglandins play a major part in the sensitisation process.

As with the periphery, the dorsal horn of the spinal cord contains many transmitters and receptors. Various receptors and subtypes are involved at the spinal level, but is is the N-methyl-D-aspartate (NMDA) receptor that has attracted most attention. The excitatory aminoacids are the major class of excitatory transmitter in the central nervous system have an important role in the spinal mechanisms of pain transmission and in the synaptic events that lead to central sensitivity and hyperalgesia. The prolonged release of peptides, such as substance P, removes the magnesium block of the channel of the NMDA receptor allowing glutamate to activate the NMDA receptor. Activation of the NMDA receptor leadsto an entry of calcium into the neurone which can then produce other mediators, increasing the activity of enzymes to generate a cascade of further substances, such as nitric-oxide or prostanoids, which augment the state of sensibilization.

GABAergic and cholecystokinin systems may also interfere with these processes. Descending pathways that use serotonin and noradrenaline are iimplicated to control nociception. Morphine, the most known analgesic substance, exerts a powerful depressive action directly in the spinal cord, as well as at the brainstem to alter the activity if descending control systems that are projected from these sites to the spinal cord.

Prolonged stimuli produce pathological processes in the integration of the pain sensation. These excitability changes in the peripheral and central nervous system establish a profound but reversible pain hypersensitivity state. Neuropathic pain is a pathological pain, typically resulting from damage to the nervous system, characterized by a complex combination of negative symptoms or sensory deficits, such as loss of sensation, and positive symptoms, such as dysesthesia and pain. Pain is persistent or paroxysmal, independently of a stimulus. After nerve injury sodium channels begin to accumulate along the axon and result in foci of hyperexcitability and ectopic action potential discharge in injured sensory neurons. In same patients, stimulus independent pain is sympathetically maintained, due to expression of alpha-receptors which renders then sensitive to circulating cathecolamines. This is also facilitated by the sprouting of sympathetic axons into the dorsal root ganglion. Continual input to the dorsal horn as a result of spontaneous firing in C fibres sensory neurons causes sensitisation of dorsal horn neurons, which increases their excitability. As a consequence stimuli that would normally be innocuous becomes painful. Central sensitisation occurs as a result of enlargement of area in the periphery where a stimulus will activate neurons, increased response to a suprathreshold input, and previously subthreshold inputs reach threshold and initiate action potentials discharge. The role of NMDA system in central sensitisation has been established in pathological pain conditions.

The relation between aetiology, mechanisms, and symptoms in this condition is complex for the different findings reported in patients with neuropathic pain. Pain may operate through common mechanisms in different diseases, no pain mechanism is strictly related to a particular disease, one mechanism can be responsible for different symptoms, and the same symptoms may be caused by different mechanisms. Finally, no predictors indicate the development of neuropathic pain in different conditions. Neuronal function is contingent on the neuron itself and its environment, and a genetic component probably contributes to the diverse response to apparent similar lesions.