Hyperalgesia frequently results from injuries or inflammation of peripheral tissues, including nervous tissue and paradoxically also from the treatment with μ-opioid receptor agonists. Compelling evidence indicates that signal amplification in central pain pathways plays an important role for the maintenance of hyperalgesia¹. In superficial spinal dorsal horn synaptic transmission between nociceptive C-fibres and lamina I projection neurons can be potentiated for prolonged periods of time in an activity dependent manner. These forms of synaptic long-term potentiation (LTP) can be securely prevented when opioids are applied during afferent stimulation. The blockage of LTP induction by opioids is a likely mechanism or pre-emptive analgesia. Upon withdrawal from high doses of opioids, however, LTP may develop at C-fibre synapses. During the latter form of LTP induction presynaptic activity at C-fibres is depressed rather than enhanced. Despite these fundamental differences in the induction, activity dependent- and opioidergic LTP share signalling pathways. This includes the activation of NMDA receptors, the rise in postsynaptic Ca²⁺ concentration and the activation of protein kinase C. Induction of opioidergic LTP further requires postsynaptic G-protein coupling which is in contrast to the presynaptic inhibition by opioids. LTP induction is abolished by blocking the Ca²⁺ rise upon withdrawal from the opioids. It is likely that the potentiation in synaptic strength translates into enhanced pain behaviour¹. Plasticity at the first synapse in pain pathways is a promising target for the prevention and treatment of hyperalgesia of various origins.