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The aims of this study were two-fold: first, to simplify the method for creating a recently described neuropathic pain model in the rat, and second, to evaluate the effects of a number of drugs with analgesic or antihyperalgesic properties, in this model. Continuous intravenous vincristine infusion (1-100 microg kg(-1) day (-1)) for 14 days resulted in a dose dependent tactile allodynia (as measured by von Frey filaments) by 7 days at doses between 30 - 100 microg kg(-1) day (-1), with a hindlimb motor deficit observed at doses greater than 50 microg kg(-1) day (-1). No thermal hyperalgesia was observed. Systemic morphine, lidocaine, mexiletine and pregabalin (given intraperitoneally) produced significant reduction of the allodynia, while tetrodotoxin was without effect. Continuous intravenous infusion of vincristine in rats thus provides a reliable model of chemotherapy induced neuropathy which may be used in defining the mechanism and pharmacology of this clinically relevant condition.

Peripheral nerve injury can lead to a persistent neuropathic pain state in which innocuous tactile stimulation elicits pain behavior (tactile allodynia). Spinal administration of the anticonvulsant gabapentin suppresses allodynia by an unknown mechanism. In vitro studies indicate that gabapentin binds to the alpha(2)delta-1 (hereafter referred to as alpha(2)delta) subunit of voltage-gated calcium channels. We hypothesized that nerve injury may result in altered alpha(2)delta subunit expression in spinal cord and dorsal root ganglia (DRGs) and that this change may play a role in neuropathic pain processing. Using a rat neuropathic pain model in which gabapentin-sensitive tactile allodynia develops after tight ligation of the left fifth and sixth lumbar spinal nerves, we found a17-fold, time-dependent increase in alpha(2)delta subunit expression in DRGs ipsilateral to the nerve injury. Marked alpha(2)delta subunit upregulation was also evident in rats with unilateral sciatic nerve crush, but not dorsal rhizotomy, indicating a peripheral origin of the expression regulation. The increased alpha(2)delta subunit expression preceded the allodynia onset and diminished in rats recovering from tactile allodynia. RNase protection experiments indicated that the DRG alpha(2)delta regulation was at the mRNA level. In contrast, calcium channel alpha(1B) and beta(3) subunit expression was not co-upregulated with the alpha(2)delta subunit after nerve injury. These data suggest that DRG alpha(2)delta regulation may play an unique role in neuroplasticity after peripheral nerve injury that may contribute to allodynia development.

Peripheral nerve injury induces upregulation of the calcium channel α2δ-1 structural subunit in dorsal root ganglia (DRG) and dorsal spinal cord of spinal nerve-ligated rats with neuropathic pain, suggesting a role of the calcium channel α2δ-1 subunit in central sensitization. To investigate whether spinal dorsal horn α2δ-1 subunit upregulation derives from increased DRG α2δ-1 subunit and plays a causal role in neuropathic pain development, we examined spinal dorsal hornα2δ-1 subunit expression with or without dorsal rhizotomy in spinal nerve-ligated rats and its correlation with tactile allodynia, a neuropathic pain state defined as reduced thresholds to non-noxious tactile stimulation. We also examined the effects of intrathecal α2δ-1 antisense oligonucleotides on α2δ-1 subunit expression and neuropathic allodynia in the nerve-ligated rats. Our data indicated that spinal nerve injury resulted in time-dependentα2δ-1 subunit upregulation in the spinal dorsal horn that correlated temporally with neuropathic allodynia development and maintenance. Dorsal rhizotomy diminished basal level expression and blocked injury-induced expression of the spinal dorsal hornα2δ-1 subunit and reversed injury-induced tactile allodynia. In addition, intrathecal α2δ-1 antisense oligonucleotides blocked injury-induced dorsal horn α2δ-1 subunit upregulation and diminished tactile allodynia. These findings indicate that α2δ-1 subunit basal expression occurs presynaptically and postsynaptically in spinal dorsal horn. Nerve injury induces mainly presynaptic α2δ-1 subunit expression that derives from increased α2δ-1 subunit in injured DRG neurons. Thus, changes in presynaptic α2δ-1 subunit expression contribute to injury-induced spinal neuroplasticity and central sensitization that underlies neuropathic pain development and maintenance.

The calcium channel alpha2delta-1 subunit is a structural subunit important for functional calcium channel assembly. In vitro studies have shown that this subunit is the binding site for gabapentin, an anticonvulsant that exerts antihyperalgesic effects by unknown mechanisms. Increased expression of this subunit in the spinal cord and dorsal root ganglia (DRG) has been suggested to play a role in enhanced nociceptive responses of spinal nerve-injured rats to innocuous mechanical stimulation (allodynia). To investigate whether a common mechanism underlies allodynic states derived from different etiologies, and if so, whether similar alpha2delta-1 subunit up-regulation correlates with these allodynic states, we compared DRG and spinal cord alpha2delta-1 subunit levels and gabapentin sensitivity in allodynic rats with mechanical nerve injuries (sciatic nerve chronic constriction injury, spinal nerve transection, or ligation), a metabolic disorder (diabetes), or chemical neuropathy (vincristine neurotoxicity). Our data indicated that even though allodynia occurred in all types of nerve injury investigated, DRG and/or spinal cord alpha2delta-1 subunit up-regulation and gabapentin sensitivity only coexisted in the mechanical and diabetic neuropathies. Thus, induction of the alpha2delta-1 subunit in the DRG and spinal cord is likely regulated by factors that are specific for individual neuropathies and may contribute to gabapentin-sensitive allodynia. However, the calcium channel alpha2delta-1 subunit is not the sole molecular change that uniformly characterizes the neuropathic pain states.