Backil Sung

Nitric oxide mediates behavioral signs of neuropathic pain in an experimental rat model

THIS study was conducted to determine whether nitric oxide (NO) is involved in the maintenance of behavioral signs of neuropathic pain induced by tightly ligating the left L5 and L6 spinal nerves. Neuropathic rats showed behavioral signs representing mechanical allodynia, cold allodynia and cold-stress exacerbated ongoing pain. Mechanical allodynia was suppressed by Nω-nitro-L-arginine methyl ester (L-NAME; 200, 100, 50, 10μM/kg, i.p.), a nitric oxide synthase inhibitor, in a dose-dependent manner. Cold allodynia and cold-stress exacerbated ongoing pain was also attenuated by L-NAME. Neither Nω-nitro-D-arginine methyl ester (D-NAME; 200μM/kg) nor saline changed any of the neuropathic pain behaviors. These results suggested that NO plays an important role in the maintenance of the behavioral signs of neuropathic pain and is involved in common steps in the maintenance of the different modalities of pain such as mechanical allodynia and cold allodynia.

Supraspinal involvement in the production of mechanical allodynia by spinal nerve injury in rats

This study examined whether or not the production of mechanical allodynia in a rat model of neuropathic pain required an involvement of supraspinal site(s). To this aim, we assessed the effect of spinal cord section at the L1 segment level on the mechanical allodynia sign (i.e. tail flick/twitch response), which was elicited by innocuous von Frey hair stimulation of the tail after unilateral transection of the tail-innervating nerve superior caudal trunk (SCT) at the level between the S3 and S4 spinal nerves. Cord transection or hemisection of the cord ipsilateral to the injured SCT drastically (though not completely) blocked the behavioral sign of mechanical allodynia (leaving noxious pinprick-elicited tail withdrawal reflex intact), whereas sham section or contralateral hemisection of the cord was without effect. These results suggest that the generation of mechanical allodynia following partial peripheral nerve injury involves transmission of the triggering sensory signal to a site(s) rostral to the L1 segment via an ipsilateral pathway(s).

Is sympathetic sprouting in the dorsal root ganglia responsible for the production of neuropathic pain in a rat model

Partial peripheral nerve injury often results in neuropathic pain that is aggravated by sympathetic excitation and induces sympathetic nerve sprouting in both the injured nerve and corresponding dorsal root ganglia (DRGs). Presently, the functional mechanisms of the interactions between the sprouting and injured somatic afferents remain uncertain. This study was performed to see whether the sprouting in the DRGs plays a key role in the development of neuropathic pain. To this aim, we compared two groups of rats, both of which were subjected to unilateral transection of the superior and inferior caudal trunks at the level between the S1 and S2 spinal nerves, with respect to sympathetic fiber sprouting; one group showed well-developed neuropathic pain behaviors (i.e. mechanical, cold and warm allodynia signs) and the other group showed poorly-developed ones. Immuno-histochemical staining with tyrosine hydroxylase (TH) antibody of the injured S1 DRG taken from both groups of rats after behavioral tests revealed that the magnitude of penetration of TH-positive fibers into the S1 DRG was not significantly different between the two groups. These results suggest that sympathetic nerve sprouting in the injured DRG is not a key factor in the development of neuropathic pain.

Role of signals from the dorsal root ganglion in neuropathic pain in a rat model.

We examined whether signals from the neuroma or the dorsal root ganglion of the injured segment are critical for the generation of neuropathic pain. To this aim, we used a rat model of peripheral neuropathy made by transecting the inferior and superior caudal trunks at the level between the S1 and S2 spinal nerves under enflurane anesthesia. These animals displayed tail-withdrawal responses to normally innocuous mechanical stimulation applied to the tail with a von Frey hair (2 g). Also, these animals, compared to pre-surgical value, displayed shorter tail-withdrawal latencies following immersion of the tail to warm (40 degrees C) or cold (4 degrees C) water. Transection of the S1 spinal nerve between the dorsal root ganglion and neuroma did not change the behavioral signs of neuropathic pain. In contrast, S1 dorsal rhizotomy significantly reduced the behavioral signs. The data suggest that signals arising from the dorsal root ganglion cells of the injured segment, but not from the neuroma, are critical for the generation of neuropathic pain in this model.

Amount of sympathetic sprouting in the dorsal root ganglia is not correlated to the level of sympathetic dependence of neuropathic pain in a rat model

Incomplete peripheral nerve injury often leads to neuropathic pains, some of which are relieved by sympathectomy, and results in sympathetic postganglionic nerve fiber sprouting in the dorsal root ganglion (DRG). This study was performed to see whether the sprouting in the DRG plays a key role in the sympathetic dependence of neuropathic pain. To this aim, we compared two groups of rats, both of which were subjected to unilateral transection of the inferior and superior caudal trunks at the levels between the S1 and S2, S2 and S3, and S3 and S4 spinal nerves, with respect to sympathetic fiber sprouting; one group showed neuropathic pain behaviours (i.e. mechanical and cold allodynia signs) which were very sensitive to phentolamine, alpha adrenergic blocker, and the other group exhibited no sensitivity. Immuno-histochemical staining with tyrosine hydroxylase antibody of the S1-S3 DRGs was not correlated with the sensitivity to phentolamine. These results suggest that the degree of sympathetic dependence of neuropathic pain is not a function of the extent of the sympathetic postganglionic nerve fiber sprouting in the DRG.

A mouse model for peripheral neuropathy produced by a partial injury of the nerve supplying the tail

We attempted to develop a mouse model for peripheral neuropathy by a partial injury of the nerve supplying the tail. Under enflurane anesthesia, the unilateral superior caudal trunk was resected between the S3 and S4 spinal nerves. Tests for thermal allodynia were conducted by immersing the tail into 4 or 38 degrees C water. The mechanical allodynia was assessed by stimulating the tail with a von Frey hair (1.96 mN, 0.2 g). After the nerve injury, the experimental animals had shorter tail withdrawal latencies to cold and warm water immersion than the presurgical latency, and exhibited an increase in tail response to von Frey stimulation. We interpret these abnormal sensitivities as the signs of mechanical, cold and warm allodynia following the superior caudal trunk injury in the mouse.

Decrease in spinal CGRP and substance p is not related to neuropathic pain in a rat model

We tested the hypothesis that the decrease in spinal levels of SP and CGRP after peripheral nerve injury is related to neuropathic pain. We compared two groups of rats, both of which were subjected to unilateral transection of the inferior and superior caudal trunks between the S1 and S2 spinal nerves. One group exhibited well-developed neuropathic signs after the nerve injury, whereas the other group showed poorly developed signs despite the same nerve injury. The decrease in immunoreactivity of CGRP and SP in the S1 dorsal horn (injured segment) was not significantly different between the two groups. These results suggest that the decrease in spinal levels of CGRP and SP after peripheral nerve injury is not related to neuropathic pain.

Developmental characteristics of neuropathic pain induced by peripheral nerve injury of rats during neonatal period

To gain an insight into the developmental characteristics of neuropathic pain induced by peripheral nerve injury during neonatal period, we employed three groups of rats suffering from peripheral nerve injury at different postnatal times, and compared the onset time, severity and persistency of neuropathic pain behaviors, such as mechanical and cold allodynia. The first group (P0 group) was subjected to partial injury of tail-innervating nerves within 24 h after birth, the second group (P10 group) underwent nerve injury at postnatal day (P) 10, and the third group (P60 group) was subjected to injury at P60. Although mechanical allodynia was readily detectable in the P60 group even 1 day after nerve injury, the signs of neuropathic pain were observed from 6 or 8 weeks after nerve injury in the P0 or P10 groups, respectively. Compared with the P60 group, the P0 group showed more robust mechanical and cold allodynia, whereas the P10 group exhibited rather milder pains. In addition, while the P0 and P60 groups showed long-lasting signs of mechanical allodynia, the P10 group exhibited shorter persistency. These results indicate that peripheral nerve injury during neonatal period leads to neuropathic pain with distinct developmental characteristics later in life.

Increases in spinal vasoactive intestinal polypeptide and neuropeptide Y are not sufficient for the genesis of neuropathic pain in rats.

We tested the hypothesis that increases in the spinal levels of vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY) were related to the development of neuropathic pain. To this aim, we compared two groups of rats. One group showed well-developed neuropathic pain in the tail following unilateral transection of the inferior and superior caudal trunks between the S1 and S2 spinal nerves, and the other group showed poorly-developed neuropathic pain despite the same nerve injury. The increases in immunoreactivity of VIP and NPY in the S1 dorsal horn (injured segment) were not significantly different between the two groups. These results suggested that increases in the spinal levels of VIP and NPY after peripheral nerve injury were not sufficient for the development of neuropathic pain.

Some membrane property changes following axotomy in Aδ-type DRG cells are related to cold allodynia in rat

Numerous studies have suggested that changes in electrophysiological properties of primary sensory neurons after axonal injury contribute to the generation of neuropathic pain. Presently, however, it is unclear which of the changes is important. To address this issue, we performed behavioral and electrophysiological experiments in a double-blind fashion; we made intracellular recordings in the S1 dorsal root ganglia excised from rats exhibiting cold allodynia behavior after chronic S1 spinal nerve transaction (allodynia-positive group) and from rats lacking such behavior after the same nerve injury (allodynia-negative group) or sham injury (sham group). In this study, we sought which of the membrane property changes produced by the spinal nerve injury in each of C-, Adelta- and Aalpha/beta-cell populations was unique to the allodynia-positive group. Analyses of our data revealed that only some changes in Adelta-cells (e.g. the decrease in resting membrane potential and in the threshold of central process) were more pronounced in or unique to the allodynia-positive group. We concluded that certain membrane property changes in the somata and dorsal root axons of Adelta-cells might be important in the generation of cold allodynia.