Alleviation of neuropathic pain by trazodone in rats

Abstract Neuropathic pain is generally characterised by an abnormal sensation (dysesthesia), an increased response to painful stimuli (hyperalgesia), and pain in response to a stimulus that does not normally provoke pain (allodynia). The present study was designed to investigate the effect of trazodone (5mg/kg and 10mg/kg) on peripheral neuropathic pain induced by partial sciatic nerve ligation in rats. Mechanical hyperalgesia, cold allodynia and thermal hyperalgesia were assessed by performing the pinprick, acetone, and hot plate tests, respectively. Biochemically, lipid peroxidation level and total calcium levels were measured. However, trazodone administration (5 and 10 mg/ kg i.p.) for 21days significantly diminished partial sciatic nerve ligation-induced neuropathic pain along with areduction in oxidative stress and calcium levels. The results of the present study suggest that trazodone is effective in attenuating partial sciatic nerve ligation-inducedpainful neuropathic states, which may be attributed to decreased oxidative stress and calcium levels.

Cold Allodynia after C2 Root Resection in Sprague-Dawley Rats

OBJECTIVE: The purpose of this study was to evaluate pain-related behaviors after bilateral C2 root resection and change in pain patterns in the suboccipital region in rats.METHODS: Male Sprague-Dawley rats were randomly assigned to three groups (n=25/group); näive, sham, and C2 resection. Three, 7, 10, and 14 days after surgery, cold allodynia was assessed using 20 μL of 99.7% acetone. c-Fos and c-Jun were immunohistochemically stained to evaluate activation of dorsal horn gray matter in C2 segments of the spinal cord 2 hours, 1 day, 7 days, and 14 days after surgery.RESULTS: Three days after surgery, the response to acetone in the sham group was significantly greater than in the näive group, and this significant difference between the näive and sham groups was maintained throughout the experimental period (p < 0.05 at 3, 7, 10, and 14 days). Seven, 10, and 14 days after surgery, the C2 root resection group exhibited a significantly greater response to acetone than the näive group (p < 0.05), and both the sham and C2 resection groups exhibited significantly greater responses to acetone compared with 3 days after surgery. No significant difference in cold allodynia was observed between the sham and C2 root resection groups throughout the experimental period. Two hours after surgery, both the sham and C2 root resection groups exhibited significant increases in c-Fos- and c-Jun-positive neurons compared with the naive group (p=0.0021 and p=0.0358 for the sham group, and p=0.0135 and p=0.014 for the C2 root resection group, respectively). One day after surgery, both the sham and C2 root resection groups exhibited significant decreases in c-Fos -positive neurons compared with two hours after surgery (p=0.0169 and p=0.0123, respectively), and these significant decreases in c-Fos immunoreactivity were maintained in both the sham and C2 root resection groups 7 and 14 days after surgery. The sham and C2 root resection groups presented a tendency toward a decrease in c-Jun-positive neurons 1, 7, and 14 days after surgery, but the decrease did not reach statistical significance.CONCLUSION: We found no significant difference in cold allodynia and the early expression of c-Fos and c-Jun between the sham and C2 resection groups. Our results may support the routine resection of the C2 nerve root for posterior C1–2 fusion, but, further studies are needed.

Cold Allodynia after C2 Root Resection in Sprague-Dawley Rats

OBJECTIVE: The purpose of this study was to evaluate pain-related behaviors after bilateral C2 root resection and change in pain patterns in the suboccipital region in rats. METHODS: Male Sprague-Dawley rats were randomly assigned to three groups (n=25/group); näive, sham, and C2 resection. Three, 7, 10, and 14 days after surgery, cold allodynia was assessed using 20 μL of 99.7% acetone. c-Fos and c-Jun were immunohistochemically stained to evaluate activation of dorsal horn gray matter in C2 segments of the spinal cord 2 hours, 1 day, 7 days, and 14 days after surgery.

The efficacy of combination treatment of gabapentin and electro-acupuncture on paclitaxel-induced neuropathic pain

Paclitaxel, a chemotherapeutic drug, induces severe peripheral neuropathy. Gabapentin (GBT) is a first line agent used to treat neuropathic pain, and its effect is mediated by spinal noradrenergic and muscarinic cholinergic receptors. Electro-acupuncture (EA) is used for treating various types of pain via its action through spinal opioidergic and noradrenergic receptors. Here, we investigated whether combined treatment of these two agents could exert a synergistic effect on paclitaxel-induced cold and mechanical allodynia, which were assessed by the acetone drop test and von Frey filament assay, respectively. Significant signs of allodynia were observed after four paclitaxel injections (a cumulative dose of 8 mg/kg, i.p.). GBT (3, 30, and 100 mg/kg, i.p.) or EA (ST36, Zusanli) alone produced dose-dependent anti-allodynic effects. The medium and highest doses of GBT (30 and 100 mg/kg) provided a strong analgesic effect, but they induced motor dysfunction in Rota-rod tests. On the contrary, the lowest dose of GBT (3 mg/kg) did not induce motor weakness, but it provided a brief analgesic effect. The combination of the lowest dose of GBT and EA resulted in a greater and longer effect, without inducing motor dysfunction. This effect on mechanical allodynia was blocked by spinal opioidergic (naloxone, 20 μg), or noradrenergic (idazoxan, 10 μg) receptor antagonist, whereas on cold allodynia, only opioidergic receptor antagonist blocked the effect. In conclusion, the combination of the lowest dose of GBT and EA has a robust and enduring analgesic action against paclitaxel-induced neuropathic pain, and it should be considered as an alternative treatment method.

Involvement of spinal muscarinic and serotonergic receptors in the anti-allodynic effect of electroacupuncture in rats with oxaliplatin-induced neuropathic pain

This study was performed to investigate whether the spinal cholinergic and serotonergic analgesic systems mediate the relieving effect of electroacupuncture (EA) on oxaliplatin-induced neuropathic cold allodynia in rats. The cold allodynia induced by an oxaliplatin injection (6 mg/kg, i.p.) was evaluated by immersing the rat's tail into cold water (4℃) and measuring the withdrawal latency. EA stimulation (2 Hz, 0.3-ms pulse duration, 0.2~0.3 mA) at the acupoint ST36, GV3, or LI11 all showed a significant anti-allodynic effect, which was stronger at ST36. The analgesic effect of EA at ST36 was blocked by intraperitoneal injection of muscarinic acetylcholine receptor antagonist (atropine, 1 mg/kg), but not by nicotinic (mecamylamine, 2 mg/kg) receptor antagonist. Furthermore, intrathecal administration of M(2) (methoctramine, 10 µg) and M(3) (4-DAMP, 10 µg) receptor antagonist, but not M(1) (pirenzepine, 10 µg) receptor antagonist, blocked the effect. Also, spinal administration of 5-HT(3) (MDL-72222, 12 µg) receptor antagonist, but not 5-HT(1A) (NAN-190, 15 µg) or 5-HT(2A) (ketanserin, 30 µg) receptor antagonist, prevented the anti-allodynic effect of EA. These results suggest that EA may have a signifi cant analgesic action against oxaliplatin-induced neuropathic pain, which is mediated by spinal cholinergic (M(2), M(3)) and serotonergic (5-HT(3)) receptors.

Effects of Continuous Repetitive Transcranial Magnetic Stimulation on Pain Response in Spinal Cord Injured Rat

OBJECTIVE: To investigate the effects of continuous repetitive transcranial magnetic stimulation (rTMS) on pain response in spinal cord injured rat. METHOD: Forty Sprague-Dawley rats (200~250 grams, female) were used. Thoracic spinal cord (T9) was contused using New York University (NYU) spinal cord impactor. Ten gram weight rod was dropped from a height of 25 mm to produce spinal cord contusion model with moderate injury. The animals were randomly assigned to two groups: one exposed to real magnetic stimulation (real-rTMS group) and the other not exposed to magnetic stimulation (sham-rTMS group). rTMS was applied for 8 weeks. To assess the effect of continuous rTMS on below-level pain responses after spinal cord injury (SCI), the hindpaw withdrawal response for thermal stimuli, cold stimuli and mechanical stimuli were compared between two groups. RESULTS: Behavioral response for pain showed that hindpaw withdrawal response for cold stimuli was reduced significantly from 4 weeks after SCI in real-rTMS group compared with sham group (p<0.05). CONCLUSION: These results suggest that continuous rTMS may have beneficial effects on attenuation of cold allodynia after SCI, and it might be an additional non-invasive therapeutic method in patients with chronic neuropathic pain after SCI.

Long-term Follow-up of Cutaneous Hypersensitivity in Rats with a Spinal Cord Contusion

Sometimes, spinal cord injury (SCI) results in various chronic neuropathic pain syndromes that occur diffusely below the level of the injury. It has been reported that behavioral signs of neuropathic pain are expressed in the animal models of contusive SCI. However, the observation period is relatively short considering the natural course of pain in human SCI patients. Therefore, this study was undertaken to examine the time course of mechanical and cold allodynia in the hindpaw after a spinal cord contusion in rats for a long period of time (30 weeks). The hindpaw withdrawal threshold to mechanical stimulation was applied to the plantar surface of the hindpaw, and the withdrawal frequency to the application of acetone was measured before and after a spinal contusion. The spinal cord contusion was produced by dropping a 10 g weight from a 6.25 and 12.5 mm height using a NYU impactor. After the injury, rats showed a decreased withdrawal threshold to von Frey stimulation, indicating the development of mechanical allodynia which persisted for 30 weeks. The withdrawal threshold between the two experimental groups was similar. The response frequencies to acetone increased after the SCI, but they were developed slowly. Cold allodynia persisted for 30 weeks in 12.5 mm group. The sham animals did not show any significant behavioral changes. These results provide behavioral evidence to indicate that the below-level pain was well developed and maintained in the contusion model for a long time, suggesting a model suitable for pain research, especially in the late stage of SCI or for long term effects of analgesic intervention.

Antiallodynic Effect of Pregabalin in Rat Models of Sympathetically Maintained and Sympathetic Independent Neuropathic Pain

Pregabalin binds to the voltage-dependent calcium channel alphadelta subunit and modulates the release of neurotransmitters, resulting in analgesic effects on neuropathic pain. Neuropathic pain has both sympathetically maintained pain (SMP) and sympathetic independent pain (SIP) components. We studied the antiallodynic effects of pregabalin on tactile allodynia (TA) and cold allodynia (CA) in SMP-and SIP-dominant neuropathic pain models. Allodynia was induced by ligation of the L5 & L6 spinal nerves (SMP model) or by transection of the tibial and sural nerves (SIP model) in rats. For intrathecal drug administration, a PE-10 catheter was implanted through the atlantooccipital membrane to the lumbar enlargement. Pregabalin was administered either intraperitoneally (IP) or intrathecally (IT) and dosed up incrementally until an antiallodynic effect without sedation or motor impairment was apparent. TA was assessed using von Frey filaments, and CA was assessed using acetone drops. IP-administered pregabalin dose-dependently attenuated TA in both models and CA in the SMP model, but not CA in the SIP model. IT-administered pregabalin dose-dependently attenuated both TA and CA in both models. However, the dose response curve of IT-administered pregabalin in SMP was shifted to left from that of SIP and the ED50 of IT-administered pregabalin for CA in SMP was about 900 times less than that in SIP. These findings suggest that pregabalin exerts its antiallodynic effect mainly by acting at the spinal cord, and that IT-administered pregabalin has more potent antiallodynic effects in SMP. The alphadeltasubunit might be less involved in the CA in SIP.

Causalgiform pain produced by the tight ligation of L5, L6 spinal nerves in the rat / 대한마취과학회지

Causalgiform pain was produced in adult rats(Sprague-Dawley) by the tight ligation of L5 and L6 spinal nerves. To verify the causalgiform pain, we tested spontaneous pain behavior', withdrawal sensitivity to the innocuous mechanical stimulation of Von Frey hair 2.35gm(mechanical allodynia); and withdrawal frequency to the cold stimulation of acetone (cold allodynia). The natural duration of causalgiform pain (control group, N=11) and the change of pain by surgical sympathectomy (sympathectomy group, N=9) was observed. The results were as follows 1) Mechanical allodynia(57.8%) and cold allodynia(63.2%) was induced on the postoperative 7th day. 2) Causalgiform pain was continued for 3 to 5 weeks in the control group. 3) Mechanical allodynia and cold allodynia was reduced significantly (P<0.05) after surgical sympathectomy in the sympathectomy group.