Primary sensory neurons respond to peripheral stimulation and project to the spinal cord. Specifically, the population of neurons which respond to damaging stimuli terminate in the superficial layers of the dorsal horn. Therefore, the dorsal horns constitute the first relay site for nociceptive fibre terminals which make synaptic contacts with second order neurons. It has recently become clear that the strength of this first pain synapse is plastic and modifiable by several modulators, including neuronal and non-neuronal regulators, and studies on the fundamental processes regulating the plasticity of the first pain synapse have resulted in the identification of new targets for the treatment of chronic pain.