Central sensitization of the spino-parabrachial-amygdala pathway that outlasts a brief nociceptive stimulus.

KEY POINTS: Chronic pain is disabling because sufferers form negative associations between pain and activities, such as work, leading to the sufferer limiting these activities. Pain information arriving in the amygdala is responsible for forming these associations and contributes to us feeling bad when we are in pain. Ongoing injuries enhance the delivery of pain information to the amygdala. If we want to understand why chronic pain can continue without ongoing injury, it is important to know whether this facilitation continues once the injury has healed. In the present study, we show that a 2 min noxious heat stimulus, without ongoing injury, is able to enhance delivery of pain information to the amygdala for 3 days. If the noxious heat stimulus is repeated, this enhancement persists even longer. These changes may prime this information pathway so that subsequent injuries may feel even worse and the associative learning that results in pain-related avoidance may be promoted. ABSTRACT: Pain is an important defence against dangers in our environment; however, some clinical conditions produce pain that outlasts this useful role and persists even after the injury has healed. The experience of pain consists of somatosensory elements of intensity and location, negative emotional/aversive feelings and subsequent restrictions on lifestyle as a result of a learned association between certain activities and pain. The amygdala contributes negative emotional value to nociceptive sensory information and forms the association between an aversive response and the environment in which it occurs. It is able to form this association because it receives nociceptive information via the spino-parabrachio-amygdaloid pathway and polymodal sensory information via cortical and thalamic inputs. Synaptic plasticity occurs at the parabrachial-amygdala synapse and other brain regions in chronic pain conditions with ongoing injury; however, very little is known about how plasticity occurs in conditions with no ongoing injury. Using immunohistochemistry, electrophysiology and behavioural assays, we show that a brief nociceptive stimulus with no ongoing injury is able to produce long-lasting synaptic plasticity at the rat parabrachial-amygdala synapse. We show that this plasticity is caused by an increase in postsynaptic AMPA receptors with a transient change in the AMPA receptor subunit, similar to long-term potentiation. Furthermore, this synaptic potentiation primes the synapse so that a subsequent noxious stimulus causes prolonged potentiation of the nociceptive information flow into the amygdala. As a result, a second injury could have an increased negative emotional value and promote associative learning that results in pain-related avoidance.