Chronic pain after clip-compression injury of the rat spinal cord

Chronic tactile allodynia and hyperalgesia are frequent complications of spinal cord injury (SCI) with poorly understood mechanisms. Possible causes are plastic changes in the central arbors of nociceptive and nonnociceptive primary sensory neurons and changes in descending modulatory serotonergic pathways. A clinically relevant clip-compression model of SCI in the rat was used to investigate putative mechanisms of chronic pain. Behavioral testing (n = 18 rats) demonstrated that moderate (35 g) or severe (50 g) SCI at the 12th thoracic spinal segment (T-12) reliably produces chronic tactile allodynia and hyperalgesia that can be evoked from the hindpaws and back. Quantitative morphometry (n = 37) revealed no changes after SCI in the density or distribution of Abeta-, Adelta-, and C-fiber central arbors of primary sensory neurons within the thoracolumbar segments T-6 to L-4. This observation rules out a mandatory relationship between pain-related behaviors and changes in the distribution or density of central afferent arbors. The area of serotonin immunoreactivity in the dorsal horn (n = 12) decreased caudal to the injury site (L1-4) and increased threefold rostral to it (T9-11). The decreased serotonin and presence of tactile allodynia and hyperalgesia caudal to the injury are consistent with disruption of descending antinociceptive serotonergic tracts that modulate pain transmission. The functional significance of the increased serotonin in rostral segments may relate to the development of tactile allodynia as serotonin also has known pronociceptive actions. Changes in the descending serotonergic pathway require further investigation, as a disruption of the balance of serotonergic input rostral and caudal to the injury site may contribute to the etiology of chronic pain after SCI.     

The effects of noxious heat on responses of spinocervical units to low intensity cutaneous stimuli

The responses of spinocervical neurons to sinusoidal hair displacements were studied during and in the absence of radiant heating of parts of the hindpaw to noxious levels (45–65 °C). Noxious heat usually increased background discharge and lowered the signal-to-noise ratio at low frequencies of hair displacement. At higher frequencies over 20 Hz, this ratio was slightly depressed for half of the cells, and dramatically increased for the others. Similar effects were found when the heating was off the receptive field for hair displacement, which suggests a central cause for these effects.     

Centrally mediated antihyperalgesic and antiallodynic effects of zonisamide following partial nerve injury in the mouse

Some antiepileptic drugs are used clinically to relieve neuropathic pain. We have evaluated the effects and investigated the possible mechanisms of action of zonisamide, an antiepileptic drug, on thermal hyperalgesia and tactile allodynia in a murine chronic pain model that was prepared by partial ligation of the sciatic nerve. Subcutaneously administered zonisamide (10 and 30 mg/kg) produced antihyperalgesic and antiallodynic effects in a dose-dependent manner; these effects were manifested by elevation of the withdrawal threshold in response to a thermal (plantar test) or mechanical (von Frey) stimulus, respectively. Similar analgesic effects were obtained in both the plantar and von Frey tests when zonisamide was injected either intracerebroventricularly (i.c.v., 10 and 30 μg) or intrathecally (i.t., 10 and 30 μg). It is thought that this elevation of the thermal and mechanical withdrawal thresholds after local injection of zonisamide is not generated secondarily via impaired motor activity, since zonisamide (30 μg, i.c.v. or i.t.) did not affect locomotor activity, as assessed in sciatic-nerve-ligated mice. Moreover, the nitric oxide synthase inhibitor L-NAME, when injected either i.c.v. or i.t., potentiated the analgesic effects of zonisamide. In contrast, neither i.c.v. nor i.t. zonisamide produced antinociceptive effects against acute thermal and mechanical nociception in non-ligated mice. Together, following peripheral nerve injury, it appears that zonisamide produces centrally mediated antihyperalgesic and antiallodynic effects partly via the blockade of nitric oxide synthesis.     

Dysaesthesia associated with sternotomy for heart surgery

Background. Chronic pain occurs in 40–50% patients followingcardiac surgery. Dysaesthesia, either in the form of heightenedor diminished skin sensation, are frequently associated withchronic neuropathic pain. Therefore, dysaesthesia in the earlypostoperative period may predict chronic pain. However, thecharacter and causes of dysaesthesia in the early postoperativeperiod are unknown. The aim of this study was to investigatethe incidence, extent, and causes of dysaesthesia followingcardiac surgery by sternotomy. Methods. In a prospective cohort study, 50 patients undergoingsternotomy for cardiac surgery were admitted to the study: 38underwent coronary artery bypass graft (CABG), nine valve surgery,and three combined surgery. Forty-eight hours postoperatively,acute pain was measured by four-point verbal scale. Manual pinprickand cotton wool brushing was used to detect the areas of dysaesthesia. Results. Some form of dysaesthesia was found in 27 (54%) ofthe patients. Using multivariate regression analysis, the totalarea of dysaesthesia was positively associated with CABG surgeryand the severity of postoperative pain (P<0.001). Conclusion. Dysaesthesia is common in the early postoperativeperiod following cardiac surgery using a sternotomy and is associatedwith CABG surgery. The association with severity of pain mayindicate a neuropathic element that is unrelieved by conventionalopioid analgesia.      

‘Protective premedication’: an option with gabapentin and related drugs?

Substantial progress has been made during the last decades in our understanding of acute pain mechanisms, and this knowledge has encouraged the search for novel treatments. Of particular interest has been the observation that tissue injury initiates a number of modulations of both the peripheral and the central pain pathways, which convert the system from a 'physiological' to a 'pathological' mode of processing afferent information. Gabapentin, which binds to the alpha(2)delta subunit of the voltage-dependent calcium channel, is active in animal models of 'pathological' but not in models of 'physiological' pain. Consequently, attention has so far been focused on neuropathic pain as a target for the clinical use of gabapentin and analogues. Recently, several reports have indicated that gabapentin may have a place in the treatment of post-operative pain. This article presents a brief summary of the potential mechanisms of post-operative pain, and a systematic review of the available data of gabapentin and pregabalin for post-operative analgesia. It is concluded that the results with gabapentin and pregabalin in post-operative pain treatment published so far are promising. It is suggested that future studies should explore the effects of 'protective premedication' with combinations of various antihyperanalgesic and analgesic drugs for post-operative analgesia.     

Cyclooxygenase inhibitors and thalidomide ameliorate vincristine-induced hyperalgesia in rats

In this study ibuprofen (50.0 mg/kg, i.p.), rofecoxib (10.0 mg/kg, i.p.) and thalidomide (50.0 mg/kg, oral) were shown to prevent vincristine-induced mechanical hyperalgesia. Sprague-Dawley rats were injected every other day with vincristine (0.1 mg/kg) over 13 days. The animals were cotreated daily with vehicle (saline), ibuprofen, rofecoxib or thalidomide throughout the period of vincristine treatment. Mechanical withdrawal threshold to punctuate and radiant heat stimuli were determined prior to and then on alternate days throughout the treatment period. Vincristine vehicle-treated animals developed marked mechanical hyperalgesia from day 5 of chemotherapy and this lasted until the end of the experiment. Thermal thresholds were not altered by the administration of vincristine vehicle. Animals in the vincristine vehicle group neither gained nor lost weight during the treatment period. All three active drugs showed an antihyperalgesic effect on the responses to mechanical stimulation of the hind paw that was significant from day 5 for ibuprofen and thalidomide and from day 7 for rofecoxib. Thermal thresholds increased after the administration of both the NSAIDs and thalidomide. Rofecoxib was the only drug to show any beneficial effect in protecting the animals from failure to gain body weight.     

鞘内注射JNK特异性抑制剂SP600125对CCI大鼠痛行为的影响

Objective To observe the effect of intrathecal administration of SP600125 on both MWT and TWL of rats after chronic constriction injury (CCI) of the sciatic nerve. Methods 40 male SD rats were randomized to deride into 5 groups (n=8). Rats in group SP5 received SP600125 5 μg after CCI; rats in group SP25 received SP600125 25 μg after CCI; rats in group SP50 received SP600125 50 μg after CCI; rats in group DMSO received 2% DMSO 10 μl after CCI; rats in group Naive received SP600125 50 μg without sciatic nerve injury. SP600125 was dissolved in 10 μl 2%DMSO solvent. On the 7th day after CCI, MWT and TWL were determined with yon Frey filaments and thermal radiation apparatus repectively after intrathecal administration of SP600125. Results Intrathecal administration certain dosage of SP600125 could attenuate the established mechanical allodynia and thermal hyperalgesia induced by CCI rather than normal rats. Conclusion Intrathecal administration certain dosage of SP600125 could attenuate the established mechanical allodynia and thermal hyperalgesia induced by CCI.     

Experimental occlusal interference induces long-term masticatory muscle hyperalgesia in rats

Temporomandibular joint or related masticatory muscle pain represents the most common chronic orofacial pain condition. Patients frequently report this kind of pain after dental alterations in occlusion. However, lack of understanding of the mechanisms of occlusion-related temporomandibular joint and muscle pain prevents treating this problem successfully. To explore the relationship between improper occlusion (occlusal interference) and masticatory muscle pain, we created an occlusal interference animal model by directly bonding a crown to a maxillary molar to raise the masticating surface of the tooth in rats. We raised the occlusal surface to three different heights (0.2, 0.4, and 0.6 mm), and for one month we quantitatively measured mechanical nociceptive thresholds of the temporal and masseter muscles on both sides. Results showed a stimulus–response relationship between the height of occlusal interference and muscle hyperalgesia. Removal of the crown 6 days after occlusal interference showed that the removal at this time could not terminate the 1 month duration of mechanical hyperalgesia in the masticatory muscles. Lastly, we systemically administered NMDA antagonist MK801 (0.2, 0.1, and 0.05 mg/kg) to the treated rats and found that MK801 dose dependently attenuated the occlusal interference-induced hyperalgesia. These findings suggest that occlusal interference is directly related to masticatory muscle pain, and that central sensitization mechanisms are involved in the maintenance of the occlusal interference-induced mechanical hyperalgesia.     

Diurnal variation of abdominal motor responses to colorectal distension and plasma cortisol levels in rats

Most patients with functional bowel disorders complain of daytime symptoms while they remain asymptomatic at night. As symptoms are associated with heightened visceral sensitivity, we hypothesized that circadian fluctuations of the visceral sensory function occur. At four different timepoints (06.00, 12.00, 18.00 and 24.00 h), colorectal distensions (CRD) were performed in fasting conscious male Lewis rats using a balloon catheter and a barostat device. The abdominal wall contractions (behavioural pain response) were assessed during colorectal distension by abdominal wall electromyography (EMG). Plasma levels for endogenous cortisol were determined simultaneously at these timepoints. EMG responses to CRD were significantly (P < 0.05) higher at midnight and in the early morning. Plasma cortisol levels peaked in the evening. In night-active Lewis rats, the behavioural pain response to noxious visceral stimulation is augmented at night and fluctuations of visceral sensitivity are accompanied by circadian changes of plasma concentrations of endogenous cortisol. We conclude that there are marked circadian fluctuations in visceral sensory functions. Thresholds are low during time periods of normal behavioural activity. These findings suggest that fluctuation of the sensory functions may be linked to the circadian variability of symptoms in patients with functional GI disorders.     

鞘内注射JNK特异性抑制剂SP600125对CCI大鼠痛行为的影响

Objective To observe the effect of intrathecal administration of SP600125 on both MWT and TWL of rats after chronic constriction injury (CCI) of the sciatic nerve. Methods 40 male SD rats were randomized to deride into 5 groups (n=8). Rats in group SP5 received SP600125 5 μg after CCI; rats in group SP25 received SP600125 25 μg after CCI; rats in group SP50 received SP600125 50 μg after CCI; rats in group DMSO received 2% DMSO 10 μl after CCI; rats in group Naive received SP600125 50 μg without sciatic nerve injury. SP600125 was dissolved in 10 μl 2%DMSO solvent. On the 7th day after CCI, MWT and TWL were determined with yon Frey filaments and thermal radiation apparatus repectively after intrathecal administration of SP600125. Results Intrathecal administration certain dosage of SP600125 could attenuate the established mechanical allodynia and thermal hyperalgesia induced by CCI rather than normal rats. Conclusion Intrathecal administration certain dosage of SP600125 could attenuate the established mechanical allodynia and thermal hyperalgesia induced by CCI.