Inflammation of peripheral tissues can lead to enhanced pain sensitivity, or hyperalgesia, but how it does so has been the subject of controversy. New findings go some way towards clearing up the conflict, showing that long-term potentiation (LTP) at synapses between nociceptive C-fibres and specific spinal projection neurons underlies the amplification of pain-related information in inflammatory hyperalgesia.
Previous studies of pain pathways, all using high-frequency stimulation (HFS) of afferent nerve fibres to induce LTP, suggest that LTP in the spinal cord induces hyperalgesia. However, the role of LTP in inflammatory hyperalgesia has been challenged because inflammation causes low-frequency discharges of afferent nerve activity, which usually induce the opposite form of synaptic plasticity, long-term depression (LTD). Could the low-frequency activity associated with inflammation induce LTP in pain pathways?
To address this question, Ikeda et al. injected a retrograde fluorescent marker into two major pain pathway projection areas — parabrachial (PB) and periaqueductal grey (PAG) — and prepared transverse spinal cord slices with the dorsal horn projection neurons in each pathway being clearly identifiable. Consistent with previous findings, electrical HFS of primary afferent nerve fibres at C-fibre strength (a high enough intensity to activate unmyelinated fibres) induced LTP at synapses between C-fibres and spino-PB neurons. Low-frequency stimulation (LFS), within the typical frequency range of C-fibres during inflammation, had no effect on synaptic strength. By contrast, HFS of primary afferents had no effect on the strength of synapses between C-fibres and spino-PAG neurons but, importantly, LFS of primary afferents at C-fibre strength induced LTP at these synapses.
The expression of either LTP or LTD at a synapse is determined by the level and time course of a rise in intracellular calcium in postsynaptic neurons: LFS usually produces a modest increase leading to LTD, whereas HFS produces a greater increase and induces LTP. In spino-PAG neurons, the elevation in intracellular calcium in response to LFS was sufficient to induce LTP. Indeed, blocking this rise with calcium chelators abolished LFS-induced LTP, whereas blocking the release of intracellular calcium stores through inositol-1,4,5-trisphosphate receptors converted LTP into LTD.
Moreover, the subcutaneous injection of diluted formalin or capsaicin, or electrical LFS of sciatic nerve at C-fibre strength — all triggers for the induction of inflammatory hyperalgesia — induced a strong rise in calcium concentration in superficial dorsal horn neurons, and a slowly developing LTP, in deeply anaesthetized adult rats with intact spinal cords. Therefore, the low-frequency afferent barrage that naturally occurs during inflammation is sufficient to raise calcium to a critical level for the induction of LTP at synapses in the dorsal horn in vivo.
These findings reveal a synaptic pain amplifier in the dorsal horn of the spinal cord, at the first synapse in pain pathways, that is turned on by low-level activity in nociceptive fibres — a discharge pattern characteristic of inflammation — providing a solution to the question of how inflammation causes hyperalgesia.
