Inflammatory pain is a debilitating condition that can occur following tissue injury or
inflammation and results in touch evoked pain (allodynia), exaggerated pain
(hyperalgesia) and spontaneous pain, yet the neural plasticity underlying these
symptoms is not fully understood. However, it is known that lamina I neurokinin 1
receptor expressing (NK1R+) spinal cord output neurons are crucial for the
manifestation of inflammatory pain. There is also evidence that the afferent input to
and the postsynaptic response of these neurons may be altered in inflammatory pain,
which could be relevant for inflammatory pain hypersensitivity. Therefore, the aim of
this thesis was to study inflammatory pain spinal plasticity mechanisms by
investigating the synaptic input to lamina I NK1R+ neurons. In ex vivo spinal cord
and dorsal root preparations from the rat, electrophysiological techniques were used
to assess inflammation-induced changes in and pharmacological manipulation of the
primary afferent drive to lamina I NK1R+ neurons.
The excitatory input to lamina I NK1R+ neurons was examined and it was found that
inflammation did not alter the relative distribution of the type of primary afferent
input received and did not potentiate monosynaptic A δ or monosynaptic C-fibre
input, the predominant input to these neurons. Spontaneous excitatory input was
significantly elevated in the subset of neurons that received monosynaptic A δ-fibre
input only, regardless of inflammation.
It has recently been shown that the chemerin receptor 23 (ChemR23) represents a
novel inflammatory pain target, whereby ChemR23 agonists can decrease
inflammatory pain hypersensitivity, by a mechanism that involves the attenuation of
potentiated spinal cord responses. This study has found that the ChemR23 agonist,
chemerin, attenuated capsaicin potentiation of excitatory input to lamina I NK1R+
neurons and significantly reduced monosynaptic C-fibre input to a subset of these
neurons in inflammatory pain. However, chemerin was without effect in
non-potentiated conditions.
In exploring potential inflammatory pain spinal plasticity mechanisms, I have
investigated a phenomenon called activity-dependent slowing (ADS), whereby
repetitive stimulation of C-fibres at frequencies of 1Hz or above results in a
progressive slowing of action potential conduction velocity, which manifests as a
progressive increase in response latency. This is proposed to limit nociceptive input to
the spinal cord, thus regulating plasticity. Results demonstrate that inflammation
significantly attenuated C-fibre ADS in isolated dorsal roots. Furthermore, ADS in
monosynaptic C-fibre input to lamina I NK1R+ neurons was significantly reduced in
inflammatory pain, which could facilitate nociceptive drive to these key spinal cord
output neurons and promote inflammatory pain spinal cord plasticity.
In conclusion, the major novel findings of this thesis are firstly, that chemerin can
attenuate primary afferent input to lamina I NK1R+ neurons in potentiated conditions,
which supports recent studies that suggest ChemR23 is a potential target for the
development of new analgesics. Secondly, it was discovered that ADS in
monosynaptic C-fibre inputs to lamina I NK1R+ neurons is altered in inflammatory
pain, which could be relevant for inflammatory pain spinal plasticity. The findings
presented in this thesis could contribute to the development of novel inflammatory
pain treatments