Sensitization

Sensitization is an example of non-associative learning in which the progressive amplification of a response follows repeated administrations of a stimulus (Bell et al., 1995). An everyday example of this mechanism is the repeated tonic stimulation of peripheral nerves that will occur if a person rubs his arm continuously. After a while, this stimulation will create a warm sensation that will eventually turn painful. The pain is the result of the progressively amplified synaptic response of the peripheral nerves warning the person that the stimulation is harmful. Sensitization is thought to underlie both adaptive as well as maladaptive learning processes in the organism.

Types of sensitization
Sensitization primarily refers to AMPA receptor-associated sensitization. However, there are others as well, e.g. sensitization in drug addiction.

AMPA associated
A common mechanism for the AMPA receptor-associated types of sensitization is the activation of AMPA receptors on the post-synaptic membrane. Repeated stimulation of the pre-synaptic neuron will cause glutamate to be released into the synaptic cleft. The increased release of glutamate will activate the AMPA receptors. AMPA receptors will allow for additional Na+ to enter the post-synaptic neuron, thus increasing its depolarization. This will cause the post-synaptic neuron to fire continuously, thereby creating a prolonged response. It is possible that the intensity of the stimulation is what distinguishes the different types of sensitization, in that kindling may require more intense stimulation than LTP. Another possibility are alterations in the function of inhibiting GABAergic neurons. This, however, has not been established (McEarchern & Shaw, 1999).


 * For example, electrical or chemical stimulation of the rat hippocampus causes strengthening of synaptic signals, a process known as long-term potentiation or LTP (Collingridge, Isaac & Wang, 2005). LTP is thought to underlie memory and learning in the human brain.


 * A different type of sensitization is that of kindling, where repeated stimulation of hippocampal or amygdaloid neurons in the limbic system eventually leads to seizures in laboratory animals. Having been sensitized, very little stimulation is required to produce the seizures. Thus, kindling has been suggested as a model for temporal lobe epilepsy in humans, where stimulation of a repetitive type (flickering lights for instance) can cause epileptic seizures (Morimoto, Fahnestock & Racine, 2004). Often, people suffering from temporal lobe epilepsy report symptoms of negative affect such as anxiety and depression that might result from limbic dysfunction (Teicher et al., 1993).


 * A third type is central sensitization, where nociceptive neurons in the dorsal horns of the spinal cord become sensitized by peripheral tissue damage or inflammation (Ji et al., 2003). This type of sensitization has been suggested as a possible causal mechanism for chronic pain conditions. These various types indicate that sensitization may underlie both pathological and adaptive functions in the organism.

Other

 * Drug sensitization occurs in drug addiction, and causes is an increase in the sensitivity to a substance. It involves delta FosB and may be responsible for the high incidence of relapse that occur in treated drug addicts

Etiology
Sensitization has been implied as a causal or maintaining mechanism in a wide range of apparently unrelated pathologies including substance abuse and dependence, allergies, asthma, and some medically unexplained syndromes such as fibromyalgia and multiple chemical sensitivity. Sensitization has also been suggested in relation to psychological disorders such as post-traumatic stress disorder, panic anxiety and mood disorders (Rosen & Schulkin, 1998; Antelman, 1988; Post, 1992).

History
Eric Kandel was one of the first to describe sensitization based on his experiments observing gill withdrawal of the seasnail Aplysia in the 1960s and 1970s. Kandel and his colleagues showed that after habituation from siphon touching (gill withdrawal response weakened), applying a paired noxious electrical stiumlus to the tail and a touch to the siphon, gill withdrawal was once again noted. After this senitization, applying a light touch to the siphon, absent of noxious stimulus to the tail, Aplysia produced a strong gill withdrawal response. When tested several days after the initial trials, this response was still manifest (After Squire and Kandel, 1999). In 2000, Eric Kandel was awarded the Nobel Prize in Physiology or Medicine for his research in neuronal learning processes.