Sciatic Nerve Section In Rats Research Articles

Atorvastatin is beneficial for muscle reinnervation after complete sciatic nerve section in rats

Nerve regeneration and functional recovery are often incomplete after peripheral neurotmetic lesion. Atorvastatin has been shown to be neuroprotective after transient ischaemia or traumatic injury. The aim of this study was to establish if systemic administration of Atorvastatin could improve functional muscle reinnervation after complete sciatic nerve section. Sixteen female Sprague-Dawley rats were used in this study. After a complete right sciatic nerve section, end-to-end microsuture repair was performed and fibrin glue was added. Three groups were studied: (1) sutures (S) + fibrin glue (F) only + saline administration for 14 days; (2) S+F+Atorvastatin administration for 14 days; and (3) uninjured nerve. Five months later, the sciatic nerve and the gastrocnemius muscle were isolated to perform in vivo electrophysiological measurements. Better kinematics was observed in atorvastatin-treated rats 5 months after its administration. Indeed, a larger excursion of the hip-ankle-toe angle during walking was observed. This effect was associated with the preservation of electromyographic activity (2.91 mV vs 0.77 mV) and maximal muscle force (85.1 g vs 28.6 g) on stimulation of the proximal nerve section. Five months after a neurotmetic lesion, the recovery is incomplete when using suture and fibrin glue only. Furthermore, the systemic administration of Atorvastatin for 14 days after lesion was beneficial in improving locomotion capability associated with the re-establishment of muscle strength and EMG activity.

Behavioral Manifestation of Neuropathic Pain Following Sciatic Nerve Section in Rats

The present study was performed to observe the time course of behavioral signs of painful sensations in sciatic neurectomy animal model and to test the effects of sympathectomy and saphenous nerve section on these behavioral signs. Sciatic nerve was ligated and cut at the mid-thigh level under gaseous anesthesia. The application of von Frey filaments to the medial plantar surface of foot revealed weak and long-lasting mechanical allodynia (until end of test period, 20 weeks PO). Acetone application to the plantar surface of foot was used ti measure the sensitivity to cold stimulation. Cold allodynia which is interpreted as increased response to acetone application developed fairly well and lasted the end of test period (20 weeks PO). The cumulative duration of foot lifts off neutral or cold plate was used to test spontaneous, ongoing pain and was increased until 16 weeks PO and 20 weeks PO respectively. These results suggest that sciatic neurectomy which has been widely used as chronic pain model shows behavioral signs suggsting painful sensations except autotomy, which has been used as index of pain in experimental animal. Surgical sympathectomy performed 1 week after sciatic neurectomy partially reduced the behavioral signs of mechanical allodynia and cold allodynia, suggesting behavioral changes developed following section of sciatic nerve was partially sympathetic dependent. Saphenous nerve section 1 week after sciatic neurectomy almost completely reduced mechanical allodynia and cold allodynia, but did not change spontaneous, ongoing pain. These results suggest that evoked responses such as mechanical and cold allodynia are mediated by saphenous nerve activity and activating and/or maintaining mechanisms of spontanous, ongoing pain and evoked pain may be different.

A substance P receptor (NK 1) antagonist can reverse vascular and nociceptive abnormalities in a rat model of complex regional pain syndrome type II

Sciatic nerve section in rats evokes chronic hindlimb edema, pain behavior, and hyperalgesia, a syndrome resembling complex regional pain syndrome (CRPS II) in man. Furthermore, there is an increase in spontaneous protein extravasation in the hindpaw skin of rats after sciatic transection, similar to the increased protein extravasation observed in the edematous limbs of CRPS patients. Now we demonstrate that sciatic nerve section also generates chronic hindlimb warmth, distal articular tenderness, allodynia, and periarticular osteoporosis, sequelae of nerve injury resembling those observed in CRPS. We postulated that facilitated substance P signaling may contribute to these vascular and nociceptive abnormalities and attempted to reverse these changes with the long acting substance P receptor (NK 1) antagonist LY303870. Hindpaw spontaneous extravasation was inhibited by LY303870. Systemic administration of LY303870 also reversed hindpaw edema and cutaneous warmth. Intrathecal, but not systemic administration of LY303870 reversed soft tissue and articular mechanical hyperalgesia in the hindpaw. Collectively, these data further support the hypothesis that the sciatic nerve transection model closely resembles CRPS and that substance P contributes to the spontaneous extravasation, edema, warmth, and mechanical hyperalgesia observed in this model.

Glucocorticoid inhibition of neuropathic limb edema and cutaneous neurogenic extravasation

Sciatic nerve section in rats evokes chronic limb edema, pain behavior, and hindpaw hyperalgesia, a syndrome resembling the complex regional pain syndrome type II (CRPS II or causalgia) in man. Glucocorticoids such as methylprednisolone (MP) have been used as analgesic and anti-edematous agents in patients suffering from CRPS, and interestingly these therapeutic effects appear to persist in some patients after stopping the medication. Similar to the CRPS clinical response to glucocorticoids, we now demonstrate that chronic hindpaw edema in the sciatic transection CRPS model is reversed by a continuous infusion of MP (3 mg/kg/day over 21 days), and this anti-edematous effect persists for at least 1 week after discontinuing MP. Furthermore, there is a chronic increase in spontaneous protein extravasation in the hindpaw skin of rats after sciatic transection, similar to the increased protein extravasation observed in the edematous hands of CRPS patients. A 2-week infusion of MP (3 mg/kg/day) reduced spontaneous protein extravasation in the hindpaw skin by 80%. We postulated that increased spontaneous neurogenic extravasation resulted in development of limb edema in both the animal model and the CRPS patient, and that the anti-edematous effects of MP are due to an inhibition of spontaneous extravasation. Additional experiments examined the inhibitory effects of MP infusion on electrically-evoked neurogenic extravasation in the hindpaw skin of normal rats. MP inhibition was dose- and time-dependent, with an ED 50 of 1.2 mg/kg/day for a 14-day continuous infusion of MP, and a maximum inhibitory effect requiring 17 days of MP infusion (3 mg/kg/day). MP (3 mg/kg/day for 14 days) also blocked both capsaicin- and SP-evoked neurogenic extravasation, indicating a post-junctional inhibitory effect. Our interpretation is that increased spontaneous neurogenic extravasation in this CRPS model contributed to the development and maintenance of hindpaw edema, and that chronic MP administration dose- and time-dependently blocked neurogenic extravasation at a post-junctional level, thus reversing spontaneous extravasation and limb edema in this model.

Methylprednisolone prevents the development of autotomy and neuropathic edema in rats, but has no effect on nociceptive thresholds

Corticosteroids are probably an effective treatment for some types of neuropathic pain and complex regional pain syndromes. This study examined the effects of systemic methylprednisolone (MP) on acute nociception and on pain behavior and hyperalgesia in normal and neuropathic rats. There was no dose-response to intraperitoneal MP (up to 12 mg/kg) for nociceptive thresholds to heat (Peltier) or mechanical (analgesy-meter and von Frey fibers) stimuli in normal rats. Chronic high dose MP (3 mg/kg per day for 21 days) also had no effect on acute nociceptive thresholds in normal rats. After sciatic nerve section in rats a saphenous nerve mediated hyperalgesia to heat and mechanical stimuli gradually developed over 21 days. High dose MP (3 mg/kg per day for 21 days) had no effect on this adjacent neuropathic hyperalgesia. When systemic MP was started immediately after bilateral sciatic and saphenous nerve transection there was a dose-dependent reduction in autotomy behavior. Substance P has been proposed as a mediator of neuropathic pain and edema. Single dose MP (12 mg/kg) slightly reduced the substance P mediated extravasation induced with electrical stimulation of the saphenous nerve. Chronic MP (3.4 mg/kg per day for 28 days) severely reduced the neurogenic extravasation induced with saphenous nerve stimulation. Sciatic sectioned rats developed hindpaw edema between 7 and 14 days after surgery, and this neuropathic edema did not develop in rats chronically treated with MP (3.4 mg/kg per day). These results demonstrate that corticosteroids did not affect nociceptive thresholds in normal or neuropathic hyperalgesic rats. Chronic steroid treatment did prevent the development of autotomy and neuropathic edema, and completely blocked neurogenic extravasation, findings consistent with the hypothesis that primary afferent substance P release mediates autotomy pain behavior and neuropathic edema. This may be a relevant model for examining the effects of corticosteroids on neuropathic pain and complex regional pain syndromes.

Effects of peripheral axotomy on cholecystokinin neurotransmission in the rat spinal cord.

Because cholecystokinin (CCK) acts as a "functional" endogenous opioid antagonist, it has been proposed that changes in central CCKergic neurotransmission might account for the relative resistance of neuropathic pain to the analgesic action of morphine. This hypothesis was addressed by measuring CCK-related parameters 2 weeks after unilateral sciatic nerve section in rats. As expected, significant decreases (-25-38%) in the tissue concentrations and in vitro release of both substance P and calcitonin gene-related peptide were noted in the dorsal quadrant of the lumbar spinal cord on the lesioned side. In contrast, the tissue levels and in vitro release of CCK were unchanged in the same area in lesioned rats. Measurements in dorsal root ganglia at L4-L6 levels revealed no significant changes in proCCK mRNA after the lesion. However, sciatic nerve section was associated with a marked ipsilateral increase in both CCK-B receptor mRNA levels in these ganglia (+70%) and the autoradiographic labeling of CCK-B receptors by [3H]pBC 264 (+160%) in the superficial layers of the lumbar dorsal horn. Up-regulation of CCK-B receptors rather than CCK synthesis and release probably contributes to increased spinal CCKergic neurotransmission in neuropathic pain.

The depressive effect of intrathecal clonidine on the spinal flexor reflex is enhanced after sciatic nerve section in rats

The effect of intrathecal (i.t.) α 2-adrenoceptor agonist, clonidine, on the spinal nociceptive flexor reflex was studied in decerebrate, spinalized, unanesthetized rats with intact sciatic nerves or in rats in which the sciatic nerve had been ipsilaterally sectioned. In rats with intact nerves i.t. clonidine caused a dose-dependent biphasic effect on flexor reflex excitability. At low dose (10 ng) the effect of clonidine was purely facilitatory, whereas with 50–100 ng clonidine the initial facilitation was often followed by reflex depression. Long-lasting, strong reflex depression was observed after i.t. injection of high doses of clonidine (1 and 10 μg). Four to 18 days after sciatic nerve section, the depressive effect of clonidine on the flexor reflex was dramatically enhanced. Depression was frequently observed already with doses of 5 and 10 ng, and maximal depression was reached at 100 ng and 1 μg in axotomized rats. The facilitatory effect of low doses of clonidine on the reflex was also observed, although somewhat less frequently than in normals. The depressive effect of clonidine on the flexor reflex was reversed by the selective α 2-receptor antagonist, atipamezole (20 μg i.t.), in rats with both intact and sectioned sciatic nerves. The present results revealed an increased sensitivity and effectiveness of the depression of spinal reflex mechanisms by i.t. clonidine after sciatic nerve section, which is opposite to the decreased sensitivity to i.t. morphine after axotomy that we observed previously. Since the flexor reflex is evoked by the activation of afférents that may be the source of neuropathic pain after nerve lesion, the results support the usefulness of i.t. clonidine in treating pain associated with peripheral nerve injury.

Adjacent neuropathic hyperalgesia in rats: A model for sympathetic independent pain

Following sciatic nerve section in rats a saphenous nerve mediated adjacent neuropathic hyperalgesia (ANH) develops in response to pressure. This study demonstrates that a similar ANH to heat stimuli develops over the medial dorsum of the hindpaw (MDH) following sciatic section. A similar neuropathic hyperalgesia, with an associated pain syndrome, is seen in man following peripheral nerve section. When chronic bilateral ANH rats were unilaterally injected intradermally over the MDH with noradrenaline (NA), and with vehicle over the contralateral MDH, no side to side pressure or heat withdrawal threshold differences were observed. Likewise, no changes in pressure or heat withdrawal thresholds occurred in chronic ANH rats following chemical sympathectomy with 6-hydroxydopamine (6-OHDA). A similar pattern was seen in control rats treated with NA and 6-OHDA. The pressure and heat ANH seen in the rat was not dependent on sympathetic outflow, and thus provides an animal model for sympathetic independent pain (SIP). Sympathetic modulation was also ineffective on control rat nociceptive thresholds, which is in agreement with prior behavioral findings (Nature, 323 (1986) 158–160).

The threshold for the depressive effect of intrathecal morphine on the spinal nociceptive flexor reflex is increased during autotomy after sciatic nerve section in rats

The effect of intrathecal (i.t.) morphine on the spinal nociceptive flexor reflex in doses ranging between 10 ng and 10 μg was studied in decerebrate, spinalized, unanesthetized rats with intact sciatic nerves or in rats in which the sciatic nerve had been unilaterally sectioned. In rats with intact nerves the initial effect of i.t. morphine on the flexor reflex was a brief facilitation followed by depression. The threshold dose of morphine for reflex depression was 100 ng. In animals which did not develop autotomy after nerve section or in which autotomy had ceased for several days prior to the acute experiments i.t. morphine had a similar depressive effect on the flexor reflex as in animals with intact nerves. However, in rats which were autotomizing at the time of the acute experiment, the threshold dose of the depressive effect of morphine was increased 3–5 fold. With higher doses of morphine (1–3 μg), similar depression of the reflex was found in all groups. The present results revealed a decreased sensitivity of spinal reflex mechanisms to low, but not high, doses of morphine after sciatic nerve section accompanied by autotomy. Nerve section per se did not alter opioid sensitivity. Thus, decreased effectiveness of morphine in this model for neuropathic pain may be partially due to a desensitization to the analgesic action of opioids in the spinal cord. Since after sciatic nerve section there is a differential sensitivity to the antinociceptive effect of i.t. morphine between autotomizing and non-autotomizing rats, it is further suggested that autotomy after peripheral nerve section in rats is a useful model for the study of neuropathic pain.

The development of chronic mechanical hyperalgesia, autotomy and collateral sprouting following sciatic nerve section in rat

The development of mechanical hyperalgesia over the tarsometatarsal joints subsequent to chronic sciatic section was studied in rats. Mechanical thresholds began to drop within 7 days of sciatic section and continued to decline for 2–3 weeks, resulting in significant hyperalgesia over the original saphenous and sciatic border zones lasting up to 310 days. Contralateral hyperalgesia, which is seen in tissue injury mechanical hyperalgesia, failed to develop. Collateral sprouting of high-threshold mechanoreceptors from the saphenous nerve into the denervated deep and cutaneous tissue was observed. The extent of cutaneous sprouting did not significantly correlate with the severity of hyperalgesia. The simultaneous uniform reduction of mechanical thresholds across all tarsometatarsal areas after chronic sciatic section is consistent with a central modulation of nociceptive afferent input. The severity and temporal development of the hyperalgesia strongly correlated with the extent of autotomy behavior. This animal model of chronic mechanical hyperalgesia following peripheral nerve section closely resembles a human neuropathic pain syndrome and may provide an experimental opportunity to advance our understanding of the neuropathology subserving chronic pain.

The role of the neuroma in autotomy following sciatic nerve section in rats

A delay in the formation of the terminal neuroma following sciatic nerve section in rats was obtained by means of free nerve grafts sutured to the proximal stump of the sectioned sciatic nerve branches. The automutilating behaviour in these animals was statistically compared with that which follows single sciatic section and sciatic section plus end-to-end suture. The results showed that in animals with grafted nerve stumps, autotomy begins significantly later than in those with single sciatic section. However, when the self-mutilation started, it followed the same increasing evolution in both groups. These results suggest that autotomy after a nerve section is behaviour related to the aparition and nature of the terminal neuroma.

The role of the neuroma in autotomy following sciatic nerve section in rats

The role of the neuroma in autotomy following sciatic nerve section in rats

Sequential changes of sensory neuron (fluoride-resistant) acid phosphatase in dorsal root ganglion neurons following neurectomy and rhizotomy

Five to seven days after sciatic nerve section in rats, fluoride-resistant acid phosphatase (FRAP) expression in dorsal root ganglion (drg) neurons was markedly decreased. The decrease was in contrast to increased acid phosphatase which has been reported to occur in other neurons after nerve section. FRAP expression in ganglion neurons subsequently increased 14–21 days after nerve section; this preceded the restitution of enzyme expression in the spinal cord substantia gelatinosa. FRAP expression in drg neurons was not decreased after dorsal root section.