These results demonstrate that the tactile hypersensitivity in an animal model of neuropathic pain can be reversed physiologically, by removing the source of the irritation to the sciatic nerve. It was found that while removal of the cuff at 24 hours after model induction led to full recovery to baseline values, if the cuff was removed after 4 days there was also a trend toward recovery, but it was not fully achieved.
The fact that removal of the cuff at 4 days resulted in only partial recovery suggests that the presence of the cuff set in place mechanisms that persist even after the source of the nerve irritation is no longer present. This suggests further that there is a difference between a short-term and a long-term irritation or injury to the nerve in terms of hypersensitivity to tactile stimulation to the peripheral receptive fields. Thus, there remains a “shadow” hypersensitivity when the cuff is removed after 4 days.
Full recovery occurred with removal of the cuff at 24 hours, in contrast to the partial recovery observed when the cuff was removed after 4 days. This suggests that the time of removal of the irritant condition is critical, and prompts the hypothesis that there may be an optimal window of time during which intervention may reduce and even prevent the development of a chronic tactile hypersensitivity, and that in humans there may be a window of time for effective therapeutic intervention to prevent the development of a persistent neuropathic pain. This may be a critical issue in view of the relative resistance of this type of pain in humans.
As it has been established that substance P is an important neuromodulator involved in the transmission of pain, the effects of antagonists to the receptors at which substance P acts were tested. Antagonists to the tachykinin NK1
, and NK3
receptors were administered to rats with a permanent cuff. CP-96,345 (the NK1
receptor antagonist) significantly increased withdrawal thresholds on both days tested, ie, on days 6 and 21 after cuff implantation. The effect was modest, as withdrawal thresholds remained below 5 g. SR 48968, the NK2
receptor antagonist, also had a marginal effect, but only on day 17, not on day 11. These results indicate that substance P may be involved in the maintenance phase of neuropathic pain, similar to a report by Cahill and Coderre.11
In view of the observation that CP-96,345 had the most consistent effect, it was used to investigate possible mechanisms underlying the full versus partial reversibility of the model. The rationale for selecting this approach was that if it proved to be effective this might provide an avenue to explore a therapeutic approach to prevent or limit the development of neuropathic pain following peripheral nerve damage. Thus, in rats in which the cuff was to be removed 4 days after implantation, the antagonist was given starting 1 day after model induction and continuing daily until the cuff was removed at day 4. During this period there was a tendency for the readings 30 minutes after administration to be numerically higher (though not significant statistically) than those taken just before administration, possibly suggesting that a process is occurring in which NK1 receptors are involved in the induction of a state of hypersensitivity, particularly during the earliest days. Interestingly, the relative lack of an acute effect of CP-96,345 on day 4 suggests that other mechanisms may have begun to be recruited by this time. Intervention by early and repeated administration of the NK1 receptor antagonist facilitated recovery of the 4-day cuff model, within 6 days of the end of drug treatment. This supports the hypothesis that there may be a window of time during which the development of chronic pain may be prevented, and indicates that NK1 receptors may be intimately involved in establishing the permanence of hypersensitivity in this animal model of peripheral neuropathic pain. The data also support the concept that treatment for neuropathic pain should begin before the onset of symptoms whenever any damage to a nerve occurs or is suspected. Early, aggressive treatment with an appropriate drug may reduce the incidence or severity of the ensuing neuropathic pain.
Evidence from other types of trauma to the nervous system indicates that early treatment is of critical importance in determining outcome. Following a stroke, it is believed that the adequacy of treatment given in the first 24 to 48 hours is the most important factor for optimal outcome.4
Antithrombolytic medication to reestablish circulation to the affected areas of the central nervous system and thus to reduce secondary effects of the stroke, is effective only if given within 3 hours following the stroke.14
The onset of irreversible damage depends greatly on the duration and severity of ischemia.4
Neuroprotective agents are typically administered after a stroke to increase the resistance of the brain to ischemic damage.2
Following spinal cord injury, it is also standard procedure to attempt to reestablish function through early treatment.7
Evidence from basic science animal studies as well as from clinical studies suggests an overall positive clinical benefit of early surgical intervention.17
In the case of humans, surgical intervention often consists of stabilizing the spinal column to prevent further damage.6
However, acute spinal cord injury involves primary and secondary mechanisms of injury.18
While efforts are taken to reduce primary injury,19
steps are also taken to prevent the secondary injury resulting from changes in the tissues and the circulation.6
In the animal model of neuropathic pain used in this study, the presence of the sciatic nerve cuff appears to initiate processes that are fully reversible if the primary source of the injury is removed within 24 hours. However, these processes are only partially reversible if the primary injury is allowed to last for 4 days. In this case, the cuff leads to changes that persist even in its absence. As the onset of secondary mechanisms is a function of the duration of the injury, the establishment of neuropathic pain may be viewed as a degenerative process. The antagonist studies show that NK1 receptors may be involved in this degenerative process that gives rise to hypersensitivity to tactile stimulation, which is characteristic of this neuropathic pain model.
These results suggest that peripheral drive may be playing a governing role in neuropathic pain, as suggested recently.22
Spontaneous discharge in sensory fibers in models of peripheral neuropathy has been proposed in a number of models. Several studies have reported that systemic administration of lidocaine decreases ectopic activity recorded from injured peripheral sensory fibers.23
Furthermore, systematic reviews of human studies using systemic administration of local anesthetic drugs support their use for neuropathic pain.27
A governing role of afferent drive is also reflected in the data of Kim and Chung29
where nerve block transiently reversed the behavioral hypersensitivity to tactile stimulation. A predominant role of peripheral drive may also be reflected in a study by Sun and colleagues,30
who found that ectopic discharges in injured sensory nerves were highly correlated with hypersensitivity in the first 24 hours after spinal nerve ligation, and they suggest that ectopic discharge may be triggering neuropathic pain. The development of thermal and tactile hypersensitivity is permanently inhibited if spontaneous afferent activity is blocked immediately after nerve injury (for at least 3–5 days), again pointing to early spontaneous afferent activity as a trigger for pain behaviors.31
It is also interesting to note that previous studies have used the chronic constriction model of neuropathic pain, followed by decompression (removal of the ligatures) at postoperative week 4. At 8 weeks, they observed a reversal of thermal hyperalgesia and mechanical allodynia,32
an increase in the skin innervation index of substance P,33
an increase to normal levels of substance P and the δ-opioid receptor in the dorsal horn,34
and a decrease to normal levels of extracellular signal-regulated kinase (ERK) activation in the dorsal horn.32
In conclusion, these studies and our present data suggest that upon peripheral nerve injury a window of opportunity for effective medical intervention may be open, and, as time passes, the window closes progressively until, at some point, it is shut and the pain is entrenched as chronic neuropathic pain. In our model, full, spontaneous reversal with cuff removal after 24 hours but not after 4 days, and pharmacological reversal with cuff removal after 4 days, suggests that medical intervention may have a window of opportunity for effective treatment. We therefore suggest that the onset of chronic neuropathic pain is a process that occurs over several hours and days, and that effective intervention within the first few hours after nerve injury may spare a patient from a chronic debilitating neuropathic pain that may be refractory to later therapeutic interventions.