Simple withdrawal from von Frey tactile stimulation, although frequently used, is not a valid measure of peripheral nerve injury pain in rats, whereas a complex hyperalgesic-type response is a specific neuropathy-induced behavior.

Key points• The peripheral terminals of sensory neurons encode physical and chemical signals into trains of action potentials (APs) and transmit these trains to the CNS.• Although modulation of this process is thought to predominantly reside at synapses, there are also indications that AP trains are incompletely propagated past points at which axons branch. One such site is the T-junction, where the single sensory neuron axon branches into peripheral and central processes.• In recordings from sensory neurons of dorsal root ganglia excised from adult rats, we identified use-dependent failure of AP propagation between the peripheral and central processes that results in filtering of rapid AP trains, especially in C-type neurons.• Propagation failure was regulated by membrane input resistance and Ca 2+ -sensitive K + and Cl − currents. Following peripheral nerve injury, T-junction filtering is reduced in C-type neurons, which may possibly contribute to pain generation.Abstract The T-junction of sensory neurons in the dorsal root ganglion (DRG) is a potential impediment to action potential (AP) propagation towards the CNS. Using intracellular recordings from rat DRG neuronal somata during stimulation of the dorsal root, we determined that the maximal rate at which all of 20 APs in a train could successfully transit the T-junction (following frequency) was lowest in C-type units, followed by A-type units with inflected descending limbs of the AP, and highest in A-type units without inflections. In C-type units, following frequency was slower than the rate at which AP trains could be produced in either dorsal root axonal segments or in the soma alone, indicating that the T-junction is a site that acts as a low-pass filter for AP propagation. Following frequency was slower for a train of 20 APs than for two, indicating that a cumulative process leads to propagation failure. Propagation failure was accompanied by diminished somatic membrane input resistance, and was enhanced when Ca 2+ -sensitive K + currents were augmented or when Ca 2+ -sensitive Cl − currents were blocked. After peripheral nerve injury, following frequencies were increased in axotomized C-type neurons and decreased in axotomized non-inflected A-type neurons. These findings reveal that the T-junction in sensory neurons is a regulator of afferent impulse traffic. Diminished filtering of AP trains at the T-junction of C-type neurons with axotomized peripheral processes could enhance the transmission of activity that is ectopically triggered in a neuroma or the neuronal soma, possibly contributing to pain generation.

These findings indicate that nerve injury-induced electrical instability is restricted to axotomized neurons and is absent in adjacent intact neurons.

Direct injection of agents into the dorsal root ganglia (DRGs) offers the opportunity to manipulate sensory neuron function at a segmental level to explore pathophysiology of painful conditions. However, there is no described method that has been validated in detail for such injections in adult rats. We have found that 2 (µl of dye injected through a pulled glass pipette directly into the distal DRG, exposed by a minimal foraminotomy, produces complete filling of the DRG with limited extension into the spinal roots. Injection into the spinal nerve required 3 µl to achieve comparable DRG filling, produced preferential spread into the ventral root, and was accompanied by substantial leakage of injected solution from the injection site. Injections into the sciatic nerve of volumes up to 10 (µl did not reach the DRG. Transient hypersensitivity to mechanical stimulation at threshold (von Frey) and noxious levels (pin) developed after 2 µl saline injection directly into the DRG that was in part attributable to the surgical exposure procedure alone. Only minimal astrocyte activation in the spinal dorsal horn was evident after DRG saline injections. Injection of adeno-associated virus (AAV) vector conveying green fluorescent protein (GFP) transgene resulted in expression as soon as 1 day after injection into the DRG, including fibers in the spinal dorsal horn and columns. AAV injection into the DRG produced additional thermal hypersensitivity and withdrawal from the stroke of a brush and compromised motor performance. These findings demonstrate a method for selective injection of agents into single DRGs for anatomically restricted actions.

A regional approach can protect our patients from often unacceptable adverse effects produced by systematically applied drugs. Regional therapeutic approaches, as well as interventions at the level of the peripheral nervous system and particularly the dorsal root ganglion (DRG), represent an alternative to the systemic application of therapeutic agents. This article provides an overview of DRG anatomical peculiarities, explains why the DRG is an important therapeutic target, and how animal models of targeted drug delivery can help us in the translation of basic research into clinical practice.