Constriction Injury Rats Research Articles

Anti-allodynic effect of NW-1029, a novel Na + channel blocker, in experimental animal models of inflammatory and neuropathic pain

NW-1029, a benzylamino propanamide derivative, was selected among several molecules of this chemical class on the basis of its affinity for the [ 3H]batracotoxin ligand displacement of the Na + channel complex and also on the basis of its voltage and use-dependent inhibitory action on the Na + currents of the rat DRG (dorsal root ganglia) sensory neuron. This study evaluated the analgesic activity of NW-1029 in animal models of inflammatory and neuropathic pain (formalin test in mice, complete Freund's adjuvant and chronic constriction injury in rats) as well as in acute pain test (hot-plate and tail-flick in rats). Orally administered NW-1029 dose-dependently reduced cumulative licking time in the early and late phase of the formalin test (ED 50=10.1 mg/kg in the late phase). In the CFA model, NW-1029 reversed mechanical allodynia (von Frey test) after both i.p. and p.o. administration (ED 50=0.57 and 0.53 mg/kg), respectively. Similarly, NW-1029 reversed mechanical allodynia in the CCI model after both i.p. and p.o. administration yielding an ED 50 of 0.89 and 0.67 mg/kg, respectively. No effects were observed in the hot-plate and tail-flick tests up to 30 mg/kg p.o. The compound orally administered (0.1–10 mg/kg) was well tolerated, without signs of neurological impairment up to high doses (ED 50=470 and 245 mg/kg in rat and mice Rotarod test, respectively). These results indicate that NW-1029 has anti-nociceptive properties in models of inflammatory and neuropathic pain.

Increases in the concentration of brain derived neurotrophic factor in the lumbar spinal dorsal horn are associated with pain behavior following chronic constriction injury in rats

Animals exhibiting thermal hyperalgesia as a sign of neuropathic pain 7 days after loose ligation of the sciatic nerve exhibited a significant increase in the concentration of brain derived neurotrophic factor (BDNF) in their lumbar spinal dorsal horn. In contrast, following the disappearance of thermal hyperalgesia 28 days after loose ligation of the sciatic nerve, there were no differences in BDNF levels between control animals and those with sciatic ligations. These data suggest a close association in the timeline of the development and disappearance of behavioral signs of neuropathic pain with changes in BDNF levels in the lumbar spinal dorsal horn, and lend further support to the notion that plasticity in the processing of sensory information in the spinal dorsal horn may contribute to the development of persistent pain.

Intrathecal administration of the mGluR compound, ( S)-4CPG, attenuates hyperalgesia and allodynia associated with sciatic nerve constriction injury in rats

The present study examined the effects of intrathecal (i.t.) treatment (twice-daily injections on post-operative (PO) days 0–8) with the metabotropic glutamate receptor (mGluR) compound, ( S)-4-carboxyphenylglycine (( S)-4CPG), or the non-competitive N-methyl- d-aspartate (NMDA) antagonist, dizocilipine maleate (MK-801), on mechanical allodynia and cold hyperalgesia associated with chronic constriction injury (CCI) of the sciatic nerve in rats. Also, the effects of early (twice-daily injections on days 0–3) or late (twice-daily injections on days 8–11) ( S)-4CPG treatment on the injury-related mechanical allodynia and cold hyperalgesia were assessed in CCI rats. Results demonstrated that 8-day ( S)-4CPG or MK-801 treatment attenuated mechanical allodynia (up to PO days 12 or 16, respectively) and cold hyperalgesia (up to PO days 8 or 16, respectively). Results also demonstrated that early ( S)-4CPG treatment significantly attenuated the development of mechanical allodynia (90 and 270 nmol) and cold hyperalgesia (270 nmol). However, late treatment with ( S)-4CPG did not reduce the nociceptive behaviours in either behavioural task. These data not only confirm that the NMDA receptor plays a role in chronic nociception, but also suggest that Group I mGluRs are more critically involved in the development, and not the maintenance, of mechanical allodynia and cold hyperalgesia associated with CCI in rats.

The effect of continuous morphine analgesia on chronic thermal hyperalgesia due to sciatic constriction injury in rats

We employed hindfoot withdrawal latencies to radiant heat to assess the analgesic effect of prolonged morphine infusion on thermal hyperalgesia induced by chronic constriction injury (CCI) of the rat sciatic nerve. All CCI rats developed thermal hyperalgesia while sham-operated animals did not. Continuous systemic infusion of morphine dose-dependently reversed the thermal hyperalgesia in the CCI rats. In contrast, thermal hyperalgesia persisted in saline-treated CCI rats. Tolerance to morphine's analgesic effect did not develop over a period of seven days of morphine infusion, which is considered long-term for animal models. These data suggest that morphine acts rapidly and effectively to reduce behavioral signs of hyperalgesia in rats with sciatic CCI, without the concomitant development of tolerance. Scheduled administration of morphine might be an appropriate treatment regimen for relief of neuropathic pain, and the infrequent use of opioids in equivalent human clinical pain syndromes due to fear of opioid unresponsiveness and tolerance might need to be re-evaluated.

Effects of colchicine applied to the peripheral nerve on the thermal hyperalgesia evoked with chronic nerve constriction

Loose ligatures placed unilaterally on the sciatic nerve results in a thermal hyperalgesia. We applied 5 or 50 mM colchicine (COL, blocker of the fast axonal transport) to the sciatic nerve and examined the effects of COL on thermal hyperalgesia and the levels of substance P (sP), calcitonin gene-related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) in the spinal cord and the sciatic nerve. These data showed that the application of 50 mM COL to the sciatic nerve in this study functioned as an axonal transport blocker. COL abolished the hyperalgesic state in a concentration-dependent manner when applied proximal to the constriction injury. COL (50 mM), when applied distal to the injury, had no effect on the hyperalgesia. COL did not alter motor function or paw withdrawal response in the non-lesioned animal. Examination of peptide levels in nerve shows that COL resulted in an accumulation of sP, CGRP and VIP in the nerve. In the dorsal horn, COL resulted in a modest reduction in levels of sP and CGRP as compared to the non-lesioned side while VIP levels were elevated. These data suggest that active factors generated by the focal nerve compression and carried by fast axonal transport from the lesioned site to the spinal cord and/or dorsal ganglion are important in the development of thermal hyperalgesia after constriction injury in rats.

Effects of intrathecal strychnine and bicuculline on nerve compression-induced thermal hyperalgesia and selective antagonism by MK-801

We studied the effects of intrathecally administered strychnine (STR; glycine antagonist; 10 or 30 μg) and bicuculline (BIC; GABA A antagonist 1 or 3 μg) on the thermal hyperalgesia which occurs following sciatic nerve constriction injury in rats. Following unilateral application of loose ligatures around the sciatic nerve, all rats typically displayed an ipsilateral thermal hyperalgesia on day 7. Intrathecal STR or BIC administered just after the nerve lesion and on days 1 and 2 after the nerve lesion significantly enhanced in a dose-dependent fashion the magnitude of the thermal hyperalgesia normally observed on day 7, as compared to intrathecal saline (for STR: 30 μg > 10 μg ⩾ saline; for BIC: 30 μg > 10 μg ⩾ saline, p < 0.05). Intrathecal MK-801, an N- methyl- d-aspartate antagonist, was without effect upon the response latency of the normal or sham operated paw, but selectively reversed the hyperalgesia. These results suggest that the loss of a spinal STR- and BIC-sensitive inhibition augments development of the hyperalgesia induced by chronic nerve compression.

Effects of age and size on development of allodynia in a chronic pain model produced by sciatic nerve ligation in rats

Sciatic nerve constriction injury in rats has been used by various investigators as a model of chronic pain exhibiting allodynia and hyperalgesia. Although rats ranging between 200 and 350 g (40–70 days old) at the time of operation have been used by various investigators, the effect of rat age and weight on the model has not been previously studied. We noted that a group of older rats failed to develop all the characteristics of the model and designed the present study to determine the effect of age and weight on the development of allodynia and hyperalgesia. Three groups of rats varying in age (54, 71, and 107 days) and weight (220–250 g, 270–350 g, and 370–470 g) with the experimental lesion were tested for hyperalgesia, cold allodynia, and tactile allodynia. We found that although the degree of hyperalgesia of all groups was the same, the oldest group had significantly longer response latencies to allodynia tests than the younger 2 groups. Responses to the cold test were no different than control in the oldest group. The results of the present study demonstrate that larger, older rats fail to develop allodynia after sciatic nerve ligation.