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 .
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).