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receptor. This is mediated by glutamate acting on ionotropic NMDA receptors and
metabotropic glutamate receptors (mGluR), and by substance P acting on neurokinin‐1 (NK 1)
receptors. A progressive increase in action potential output from the dorsal horn cell is seen
with each stimulus, and this rapid increase in responsiveness during the course of a train of
inputs has been termed ‘wind‐up’. Long‐term potentiation (LTP) is induced by higher
frequency stimuli, but the enhanced response outlasts the conditioning stimulus, and this
mechanism has been implicated in learning and memory in the hippocampus and pain
sensitisation in the spinal cord (Sandkuhler, 2009). Behavioural correlates of these
electrophysiological phenomena have been seen in human volunteers, as repeated stimuli
elicit progressive increases in reported pain (Hansen et al, 2007).
Intense and ongoing stimuli further increase the excitability of dorsal horn neurons.
Electrophysiological studies have identified two patterns of increased postsynaptic response:
CHAPTER 1 ‘windup’ is evoked by low frequency C‐fibre (but not A‐beta fibre) stimuli and is manifest as an
enhanced postsynaptic response during a train of stimuli; and ‘LPT’ is generated by higher
frequency stimuli and outlasts the conditioning stimulus. Increases in intracellular calcium due
to influx through the NMDA receptor and release from intracellular stores activate a number
of intracellular kinase cascades. Subsequent alterations in ion channel and/or receptor activity
and trafficking of additional receptors to the membrane increase the efficacy of synaptic
transmission. Centrally mediated changes in dorsal horn sensitivity and/or functional
connectivity of A‐beta mechanosensitive fibres and increased descending facilitation
contribute to ‘secondary hyperalgesia’ (ie sensitivity is increased beyond the area of tissue
injury). Windup, LTP and secondary hyperalgesia may share some of the same intracellular
mechanisms but are independent phenomena. All may contribute to ‘central sensitisation’,
which encompasses the increased sensitivity to both C and A‐beta fibre inputs resulting in
hyperalgesia (increased response following noxious inputs) and allodynia (pain in response to
low intensity previously non‐painful stimuli) (Sandkuhler, 2009).
The intracellular changes associated with sensitisation may also activate a number of
transcription factors both in DRG and dorsal horn neurons, with resultant changes in gene and
protein expression (Ji et al, 2009). Unique patterns of either upregulation or downregulation of
neuropeptides, G‐protein coupled receptors, growth factors and their receptors, and many
other messenger molecules occur in the spinal cord and DRG in inflammatory, neuropathic
and cancer pain. Further elucidation of changes specific to different pain states may allow
more accurate targeting of therapy in the future.
In addition to the excitatory processes outlined above, inhibitory modulation also occurs
within the dorsal horn and can be mediated by non‐nociceptive peripheral inputs, local
inhibitory GABAergic and glycinergic interneurons, descending bulbospinal projections, and
higher order brain function (eg distraction, cognitive input). These inhibitory mechanisms are
activated endogenously to reduce the excitatory responses to persistent C‐fibre activity
through neurotransmitters such as endorphins, enkephalins, noradrenaline (norepinephrine)
and serotonin, and are also targets for many exogenous analgesic agents.
Thus, analgesia may be achieved by either enhancing inhibition (eg opioids, clonidine,
antidepressants) or by reducing excitatory transmission (eg local anaesthetics, ketamine).
Central projections of pain pathways
Different qualities of the overall pain experience are subserved by projections of multiple
parallel ascending pathways from the spinal cord to the midbrain, forebrain and cortex. The
spinothalamic pathway ascends from primary afferent terminals in laminae I and II, via
connections in lamina V of the dorsal horn, to the thalamus and then to the somatosensory
cortex. This pathway provides information on the sensory‐discriminative aspects of pain
4 Acute Pain Management: Scientific Evidence
