Hyperalgesia and to some degree allodynia are frequent symptoms of disease and physiological adaptations for better protection of vulnerable tissues. Enhanced sensitivity to pain may, however, persist long after the initial cause of pain has disappeared, in which case pain is no longer a symptom but rather a disease in its own right. Changes of signal processing in the nervous system may contribute to or may become the sole cause of hyperalgesia and allodynia.
Noxious stimuli excite specialized nerve endings for pain (nociceptors) which transmit the nociceptive message via thin Aδ- or C-fibers. These fibers terminate in the superficial spinal dorsal horn and form synaptic contacts with central neurons representing the first relay stations of the nociceptive pathway in the central nervous system. Here, the nociceptive information can be modified (enhanced and also attenuated) before it is further conducted to the brain [1].
Activity dependent long-lasting increase in synaptic efficacy can be observed in a subset of synapses in the brain and the spinal cord. This synaptic long-term potentiation (LTP) was first discovered in hippocampus, where it is thought to represent the cellular mechanism underlying learning and memory.
We have identified novel forms of LTP in pain pathways [2,3]. LTP at synapses between C-fibers and spinal dorsal horn neurons projecting to the midbrain periaqueductal grey (PAG) can be induced by low level presynaptic activity and by natural noxious stimuli. This finding was surprising, as induction of activity-dependent LTP at synapses in the brain requires high frequency discharges of presynaptic nerve fibers. LTP in pain pathways might cause long-lasting pain amplification under conditions of inflammation, tissue damage or nerve injury long after the initial cause of pain has disappeared.
We have thoroughly characterized this novel pain amplifier at the first synapse in pain pathways in vitro and in vivo. We have identified the types of stimuli that may trigger LTP, the signaling pathways that lead to the induction and to the maintenance of LTP, the contribution of astrocytes and microglia and the behavioral consequences of LTP at C-fiber synapses.
In collaboration with clinical colleagues we have identified perceptual correlates of LTP in pain pathways in human volunteers suggesting that activity in nociceptive C-fibers also induces synaptic LTP in humans and may underlie some forms of hyperalgesia in pain patients [4].
Interestingly we found, that spinal LTP and hyperalgesia can also be induced in the absence of any presynaptic activity in nociceptive nerve fibers. A clinically relevant example is hyperalgesia which develops after abrupt withdrawal from opioids (opioid withdrawal LTP)[5].
