SNI-related gene expression signatures were less evident in
Mrgprd-expressing and C-LTMR neurons at later timepoints,
compared with other populations in injured DRG. 3 This could be
explained by a loss of axotomized neurons of these classes and
therefore sampling of only uninjured neurons at this time-
point.24,43,64 In terms of the transcriptional response to injury,
nonpeptidergic nociceptors show enrichment of individual
proapoptotic factors early after injury,23,68 and we extend these
results in this study, by describing a subpopulation-specific
enrichment of GO terms associated with apoptosis that is evident
as early as 3 days after injury. Such data and single-cell
transcriptomic profiling of all DRG neurons following injury 37,44
may offer the opportunity to elucidate the cell death pathways
engaged and upstream effectors that enrich this process to
nonpeptidergic nociceptive neurons.
4.3. Implications for pain pathogenesis
Neuronal loss has been proposed as a key contributor to poor
functional recovery following nerve injury, 54 and biased survival of
different afferent types might be expected to contribute to
modality-specific sensory deficits. Beyond loss of function, does
DRG neuron loss contribute to chronic pain, in either an adaptive or
maladaptive manner? Intrathecal delivery of GDNF is neuro-
protective and reverses the reduction in the number of IB4-binding
DRG neurons and central terminals seen following transection. 5
Treatment is concurrently analgesic and abrogates pain-related
behaviors.7,60 However, the pleiotropic nature of GDNF makes it
impossible to directly attribute the analgesic effects to the reversal
of neuron loss. Indeed, it is possible that GDNF exerts its effect by
actions on intact nonpeptidergic nociceptive afferents,52 activation
of which is known to drive aversive behaviors in the neuropathic
state.62 These data leave the contribution of nonpeptidergic
nociceptor loss to behavior in the GDNF treatment paradigm
ambiguous. Other pharmacological approaches have been found
effective at reversing a neuronal loss in rodent models, but the
impact on pain behavior was not studied.21,22
Rodents develop marked mechanical and thermal hypersen-
sitivity rapidly following nerve injury and before timepoints at
which neuron loss is observed.10 This lack of a temporal
correlation may suggest a limited contribution to evoked hyper-
sensitivities. The temporal profile of ongoing tonic pain (eg, pain
aversiveness as measured by condition place preference
assays26) is less defined and so is its correlation to the timing of
neuron loss.
There are many anatomical sites within the somatosensory
nervous system where differential loss of sensory neuron
populations could impact neurobiology. For example, loss of
cutaneous afferents may afford more opportunity for plasticity in
reinnervation patterns, such as collateral sprouting of uninjured or
surviving afferents, and the types of nerve endings made by
different molecular subpopulations.17,27 It also seems likely that the
death of many neurons within a DRG could contribute to the
expansion and activation of immune cell types, which are known to
play a major role in neuropathic pain. 30,69 Finally, under normal
conditions, peripheral sensory input is integrated into the dorsal
horn of the spinal cord by complex interneuron circuitry. Many
spinal circuits are engaged by convergent input from different
afferent types.9,41,70 Therefore, selective loss of input from discrete
afferent types could undoubtedly impact the normal processing of
remaining afferent signals. 34 Experimentally abrogating neuronal
loss may be a fruitful approach to assess the contribution to
nervous system plasticity (adaptive or maladaptive) following injury.
In this regard, our in vitro readout would be a useful experimental
platform to help delineate the precise cell death pathways and
signaling cascades engaged (which could then be experimentally