Persistent low-frequency spontaneous discharge in A-fiber and C-fiber primary afferent neurons during an inflammatory pain condition

BACKGROUND: Primary afferent nociceptor sensitization and its accompanying spontaneous discharge are believed to be the proximate cause of the spontaneous pain and hypersensitivity that follow an acute tissue injury. Evidence for this comes almost entirely from studies limited to the first few minutes to an hour or two after injury, when the inflammatory reaction to injury has just begun. However, there is evidence that inflammatory pain mechanisms differ from acute pain mechanisms and that the mechanisms that drive and modulate inflammatory pain may evolve over time. METHODS: The authors surveyed spontaneous afferent discharge in rats with hind paw inflammation evoked by complete Freund adjuvant over the entire 14 days of the inflammatory pain condition, as determined in parallel experiments assessing allodynia and hyperalgesia. RESULTS: Inflammation-evoked heat hyperalgesia, mechanoallodynia, and mechanohyperalgesia began within hours, persisted until at least day 7, and resolved by day 14. A large percentage (23%) of A fibers had spontaneous discharge 2 days after inflammation, but the incidence was much reduced (to 7-9%) by 7 and 14 days. At all times, the A-fiber discharge frequency was low (<3.0 Hz) or very low (<0.3 Hz). A large percentage (24%) of C fibers had spontaneous discharge 2 and 7 days after inflammation, but this also declined to near control levels by day 14; C-fiber discharge frequency was also always low (most at 0.3-1.0 Hz). CONCLUSIONS: The pain, allodynia, and hyperalgesia associated with an established inflammatory condition are associated with a persistent low-frequency spontaneous discharge in both A-fiber and C-fiber sensory afferents.     

Effects of sevoflurane on carrageenan- and fentanyl-induced pain hypersensitivity in Sprague-Dawley rats

Purpose

Opioids are widely used for anesthesia but paradoxically induce postoperative pain hypersensitivity via N-methyl-d-aspartate (NMDA) receptor modulation. Sevoflurane effects on opioid-induced hyperalgesia have not been yet evaluated in vivo. Nevertheless, some experimental in vitro studies reported anti-NMDA receptor properties for sevoflurane. The aim of this study was to evaluate sevoflurane effects on fentanyl-induced hyperalgesia in opioid-naive rats and in rats with inflammatory pain.

Methods

Sevoflurane effects on hyperalgesia were evaluated in Sprague-Dawley rats: opioid-naive rats, rats treated with fentanyl (4 × 60 μg kg^?1) and rats with inflammatory pain (carrageenan) treated with fentanyl (4 × 60 μg kg^?1). On day zero, subcutaneous fentanyl injections were administered and inflammatory pain was induced with one carrageenan injection in one hind paw. Rats were exposed to low concentrations of sevoflurane (1.0 or 1.5%) on day zero prior to fentanyl injections and inflammatory pain induction, and for the duration of the fentanyl analgesic effect. The nociceptive threshold (Randall-Selitto test) was evaluated daily for 7 days. On day seven, naloxone was injected and the nociceptive threshold was assessed 5 min later.

Results

In rats without inflammatory pain but treated with fentanyl on day zero, sevoflurane 1.0% reversed the early (day zero) and long-lasting (day zero to day three) hyperalgesia classically described after high-doses of fentanyl (P < 0.05). This sevoflurane concentration antagonized the hyperalgesia induced by naloxone on day seven (P = 0.33). In a second experiment in rats with inflammatory pain, exposure to low concentrations of sevoflurane (1.0 and 1.5%) did not reduce fentanyl-induced hyperalgesia (P > 0.05), but nevertheless antagonized the naloxone induced hyperalgesia on day seven (P = 0.061).

Conclusion

Relatively low sevoflurane concentrations (1.0%) reverse fentanyl-induced hyperalgesia in rats without inflammatory pain. Nevertheless, the lack of effect of sevoflurane concentrations of 1.0% and 1.5% to oppose hyperalgesia following high-dose fentanyl and inflammatory pain suggests that sevoflurane anti-hyperalgesic properties are weak.     

神经病理性疼痛大鼠背根神经节神经元中小白蛋白的分布特征及表达变化

目的 观察神经病理性疼痛大鼠背根神经节(DRG)神经元中小白蛋白(PV)的分布特征及表达变化.方法 成年雄性SD大鼠42只,随机分为空白对照组(Control组)、假手术组(Sham组)、CCI术后1、3、5、7、14 d组,6只/组.所有动物隔日进行热、机械痛觉过敏痛觉阈值测定,行为学测试完成后取出术侧L5 DRG作冰冻切片,用免疫荧光双标技术经PV单克隆抗体和MAP-2多克隆抗体检测PV神经元的分布特征和表达变化规律.结果 (1)与Control组和Sham组比较,CCI组大鼠分别于术后1、3 d出现明显的机械、热痛觉过敏(P＜0.05),术后7 d 50%机械缩爪阈值(50%PWT)和热缩爪潜伏期(PWL)均降至最低(P＜0.01),术后14 d有所恢复,但仍低于术前水平.(2)在正常大鼠L5DRG中仅有少量PV阳性神经元,多以大型、中型神经元为主,少数为小型神经元.PV阳性神经纤维交织成网环绕在PV阴性神经元的胞体周围.(3)手术侧PV阳性神经元数目在CCI 1、3 d未见明显改变.在术后5、7 d明显减少(P＜0.05),术后14 d恢复至正常水平(P＞0.05).结论 CCI模型大鼠DRG中PV的表达水平呈时间依赖性改变,这种改变与疼痛行为学变化在时相上基本保持一致,因此推测外周感觉神经元中PV表达下降可能参与神经病理性疼痛的发展过程.     

Acute pain mechanisms.

The systems activated by tissue-injuring stimuli are complex. The nociceptive primary afferents have little spontaneous activity under normal conditions; however, after tissue injury, they display longlasting, ongoing activity. This results, in part, because the injury elicits the release of active factors that sensitize or excite the peripheral nerve terminal. A threshold that is lowered to the extent that body temperature and the pressure of edema are adequate stimuli results in spontaneous pain. This phenomenon is mediated by a variety of blood-borne active factors released during plasma extravasation, by agents released from local inflammatory cells, and by neurotransmitters released from the peripheral terminals of the primary afferent fibers themselves. Well-defined projections into the dorsal horn convey the "pain message" to at least two well-defined populations of neurons: those that are nociceptive specific and those that display an intensity-linked discharge over a range of stimuli from innocuous to noxious. Convergence from various fiber types, modalities, and end organs permits the encoding of afferent traffic with respect to intensity and location. The convergence of axons from somatic and visceral structures reflects the mechanism for the so-called "referred pain state." Most importantly, these dorsal horn systems have a dynamic component in addition to the hard-wiring; their output can be regulated both up and down. The up-regulation provides the basis for much of the facilitated processing that is believed to account for a significant percentage of the postinjury pain state. The facilitated state has a unique pharmacology, with the underlying mechanisms reflecting a cascade of actions that starts with the NMDA receptor and proceeds through the spinal release of intermediaries, such as prostaglandins and nitric oxide. Conversely, the ability to down-regulate the dorsal horn stimulus response function accounts for the powerful control exerted by a wide variety of diverse factors, including the spinal delivery of opioid and nonopioid analgesics and the "endogenous analgesia system." These linkages reflect the complexity of the encoding mechanisms that transduce the tissue injury into the behavioral sequela known as pain. This article also emphasizes that, although considerable progress has been made in the past decade, the current pace of research promises greater insights.     

Effects of gabapentin in acute inflammatory pain in humans

BACKGROUND AND OBJECTIVES: The aim of the study was to examine the analgesic effects of the anticonvulsant, gabapentin, in a validated model of acute inflammatory pain. METHODS: Twenty-two volunteers were investigated in a double-blind, randomized, placebo-controlled cross-over study. Gabapentin 1,200 mg or placebo was given on 2 separate study days. Three hours after drug administration, a first-degree burn injury was produced on the medial aspect of the nondominant calf (12.5 cm(2), 47 degrees C for 7 minutes). Quantitative sensory testing (QST) included pain ratings to thermal and mechanical stimuli (visual analog scale [VAS]), assessments of thermal and mechanical detection thresholds, and areas of secondary hyperalgesia. Side effects drowsiness and postural instability were assessed by subjective ratings (VAS). RESULTS: The burn injury induced significant primary and secondary hyperalgesia (P <.0001). Gabapentin diminished the decrease in mechanical pain threshold in the burn area (P =.04) and reduced secondary hyperalgesia, but the reduction was not significant (P =.06). Heat pain thresholds, pain during the burn, and mechanical pain in the area of secondary hyperalgesia were not significantly changed by gabapentin (P <.2). Ratings of drowsiness and unsteadiness during walking were significantly higher for gabapentin than for placebo (P <.05). CONCLUSIONS: The study indicates that gabapentin has no analgesic effect in normal skin, but may reduce primary mechanical allodynia in acute inflammation following a thermal injury. These observations suggest a clinical potential of gabapentin in the treatment of postoperative pain.     

不同传入神经损伤对大鼠神经病理性痛形成的影响及其与脊髓和背根神经节BDNF的关系

目的 探讨不同传入神经损伤对大鼠神经病理性痛形成的影响及其与脊髓和背根神经节(DRG)脑源性神经营养因子(BDNF)的关系.方法 雄性SD大鼠24只,随机分为3组(n=8):假手术组(S组)、腓肠神经损伤组(SUR组)和腓肠肌-比目鱼肌(GS)神经损伤组(GS组).SUR组和GS组分别暴露腓肠神经和GS神经并剪断,S组仅暴露腓肠神经和GS神经而不剪断.于术前1 d和术后3、7 d时测定大鼠机械痛阈.于术后7 d痛阈测定结束后,取术侧L5的DRG和脊髓节段,测定脊髓背角的BDNF表达,计算BDNF阳性神经元和受损神经元(ATF-3阳性神经元)占总DRG神经元的百分比和ATF-3阳性神经元中BDNF阳性神经元的百分比.结果 与术前1 d时比较,GS组术后各时点机械痛阈降低(P＜0.01).与S组和SUR组比较,GS组机械痛阈降低,脊髓背角BDNF表达上调,BDNF阳性神经元占总DRG神经元的百分比升高(P＜0.01);S组和SUR组各指标比较差异无统计学意义(P＞0.05).与SUR组比较,GS组ATF-3阳性神经元占总DRG神经元的百分比差异无统计学意义(P＞0.05),而ATF-3阳性神经元中BDNF阳性神经元的百分比升高(P＜0.05).结论 切断来自大鼠骨骼肌的传入神经可形成神经病理性痛,其原因与上调DRG和脊髓背角中BDNF的表达有关;而切断来自皮肤的传入神经则不会形成神经病理性痛.     

Prediction of Postoperative Pain by Preoperative Nociceptive Responses to Heat Stimulation

Background: Despite major advances in the understanding of the neurobiologic mechanisms of pain, the wide variation in acute pain experience has not been well explained. Therefore, the authors investigated the potential of a preoperatively induced heat injury to predict subsequent postoperative pain ratings in patients undergoing knee surgery.

Methods: Twenty patients were studied. The burn injury was induced 6 days before surgery with a contact thermode (12.5 cm2, 47[degrees]C for 7 min). The sensory testing, before and 1 h after the injury, included pain score during induction of the burn, secondary hyperalgesia area, thermal and mechanical pain perception, and pain thresholds. Postoperative analgesia consisted of ibuprofen and acetaminophen. Pain ratings (visual analog scale) at rest and during limb movement were followed for 10 days after surgery.

Results: The burn injury was associated with development of significant hyperalgesia. There was a significant correlation between preoperative pain ratings during the burn injury and early (0-2 days, area under the curve) and late (3-10 days, area under the curve) postoperative dynamic pain ratings during limb movement.     

Lack of Analgesia by Oral Standardized Cannabis Extract on Acute Inflammatory Pain and Hyperalgesia in Volunteers

Background: Cannabinoid-induced analgesia was shown in animal studies of acute inflammatory and neuropathic pain. In humans, controlled clinical trials with [DELTA]9-tetrahydrocannabinol or other cannabinoids demonstrated analgesic efficacy in chronic pain syndromes, whereas the data in acute pain were less conclusive. Therefore, the aim of this study was to investigate the effects of oral cannabis extract in two different human models of acute inflammatory pain and hyperalgesia.

Methods: The authors conducted a double-blind, crossover study in 18 healthy female volunteers. Capsules containing [DELTA]9-tetrahydrocannabinol-standardized cannabis extract or active placebo were orally administered. A circular sunburn spot was induced at one upper leg. Heat and electrical pain thresholds were determined at the erythema, the area of secondary hyperalgesia, and the contralateral leg. Intradermal capsaicin-evoked pain and areas of flare and secondary hyperalgesia were measured. Primary outcome parameters were heat pain thresholds in the sunburn erythema and the capsaicin-evoked area of secondary hyperalgesia. Secondary measures were electrical pain thresholds, sunburn-induced secondary hyperalgesia, and capsaicin-induced pain.

Results: Cannabis extract did not affect heat pain thresholds in the sunburn model. Electrical thresholds (250 Hz) were significantly lower compared with baseline and placebo. In the capsaicin model, the area of secondary hyperalgesia, flare, and spontaneous pain were not altered.     

Expression of neuron-associated tumor necrosis factor alpha in the brain is increased during persistent pain

BACKGROUND AND OBJECTIVES: Evidence implicates the pleiotropic cytokine tumor necrosis factor alpha (TNFalpha) in the pathogenesis of persistent pain. The present study employs a chronic constriction injury (CCI) model of neuropathic pain to examine TNFalpha production in the central nervous system (CNS) and in the periphery in this pain model. METHODS: CCI-induced hyperalgesia is assessed by measuring the nociceptive threshold using the hot-plate test. The development of hyperalgesia is correlated to levels of TNFalpha by assessing: bioactive TNFalpha in homogenates of sciatic nerves, cervical spinal cord, thoracolumbar spinal cord, as well as in plasma using the WEHI-13 variant cytotoxicity bioassay; and mRNA for TNFalpha in sections of locus coeruleus by in situ hybridization. RESULTS: We have previously demonstrated that TNFalpha bioactivity in the region of the brainstem containing the locus coeruleus is increased concurrent with the development of hyperalgesia, returning to baseline values by day 14, when hyperalgesia has ceased. Constitutive levels of TNFalpha are demonstrated in the plasma, sciatic nerves, and cervical and thoracolumbar spinal cord of control rats, sham-operated rats, and rats undergoing CCI. Levels of TNFalpha are significantly elevated in the injured sciatic nerve by day 8 postligature placement, concurrent with maximal hyperalgesia, and remain elevated when hyperalgesia has abated at day 14 postligature placement. Additionally, TNFalpha activity is increased in the thoracolumbar region of the spinal cord by day 4 postligature placement and remains elevated during hyperalgesia (day 8), as well as after hyperalgesia has dissipated (day 14). The increase in TNFalpha expression is specific to discrete regions of the CNS, rather than being the result of a systemic inflammatory response, since TNFalpha bioactivity in plasma is, in fact, decreased in rats undergoing CCI. Additionally, accumulation of mRNA specific for TNFalpha is significantly increased in neurons within a region of the brain containing the locus coeruleus at days 2, 8, and 14 postligature placement, contemporaneous with the development of hyperalgesia. CONCLUSIONS: The increases in TNFalpha within regions of the brain and spinal cord that are associated with adrenergic neuron function, as well as with modulation of pain perception, and the time course and distribution of the increases in TNFalpha accumulation support a neuromodulatory role for TNFalpha within the CNS in the development and maintenance of neuropathic pain.     

A prostaglandin E2 receptor subtype EP1 receptor antagonist (ONO-8711) reduces hyperalgesia, allodynia, and c-fos gene expression in rats with chronic nerve constriction

Chronic constriction injury (CCI) of the sciatic nerve in rats induces persistent mechanical hyperalgesia and allodynia. CCI is widely known as a model of neuropathic pain, and many studies using this model have been reported. Recently, c-fos has been used as a neural marker of pain, and various studies have assessed the relationship between hyperalgesia and c-fos expression in the lumbar spinal cord. In this study, we examined the role of a prostaglandin E2 receptor subtype EP1 receptor antagonist (ONO-8711) in a rat CCI model. EP1 receptor antagonist (EP1-ra) oral administration from day 8 to day 14 significantly reduced hyperalgesia and allodynia in the three pain tests on day 15. EP1-ra treatment from day 8 to 14 also reduced c-fos-positive cells in laminae I-II, III-IV, and V-X compared with saline treatment. A single dose of EP1-ra treatment on day 8 significantly reduced hyperalgesia and allodynia at 1 h and 2 h after administration, but the efficacy was not observed at 24 h. We conclude that EP1-ra treatment may be useful for hyperalgesia and allodynia and that EP1 receptor mechanisms are involved in the maintenance of c-fos gene expression induced by nerve injury. IMPLICATIONS: We examined whether a prostaglandin E2 receptor subtype EP1 receptor antagonist abrogates neuropathic pain induced by chronic constriction injury model in rats. The EP1 receptor antagonist significantly reduced hyperalgesia, allodynia, and c-fos positive cells. These findings suggested that EP1 receptor antagonists may have a role in treatment of neuropathic pain.     

Arthroscopic Knee Surgery Does Not Modify Hyperalgesic Responses to Heat Injury

Background: Experimental studies suggest that surgical injury may up- or down-regulate nociceptive function. Therefore, the aim of this clinical study was to evaluate the effect of elective arthroscopically assisted knee surgery on nociceptive responses to a heat injury.

Methods: Seventeen patients scheduled to undergo repair of the anterior cruciate ligament and 16 healthy controls were studied. The first burn injury was induced 6 days before surgery, and the second burn was induced 1 day after surgery with a contact thermode (12.5 cm2, 47[degrees]C for 7 min) placed on the medial aspect of the calf contralateral to the surgical side. Ibuprofen and acetaminophen were given for 2 days before the first burn injury and again from the time of surgery. In the controls, the two burn injuries were separated by 7 days. Sensory variables included cumulated pain score during induction of the burn (visual analog scale), secondary hyperalgesia area, and mechanical and thermal pain perception and pain thresholds assessed before and 1 h after the burn injury.

Results: The heat injuries induced significant increases in pain perception (P < 0.001) and decreases in pain thresholds (P < 0.02). Baseline heat pain thresholds were higher during the second burn injury in patients (P < 0.001) and controls (P < 0.01). However, there were no significant differences in pain to heat injury (P > 0.8), secondary hyperalgesia areas (P > 0.1), mechanical and thermal pain perception (P > 0.1), or mechanical and thermal pain thresholds (P > 0.08) in the burn area before surgery compared to after surgery.     

Arthroscopic knee surgery does not modify hyperalgesic responses to heat injury

BACKGROUND: Experimental studies suggest that surgical injury may up- or down-regulate nociceptive function. Therefore, the aim of this clinical study was to evaluate the effect of elective arthroscopically assisted knee surgery on nociceptive responses to a heat injury. METHODS: Seventeen patients scheduled to undergo repair of the anterior cruciate ligament and 16 healthy controls were studied. The first burn injury was induced 6 days before surgery, and the second burn was induced 1 day after surgery with a contact thermode (12.5 cm2, 47 degrees C for 7 min) placed on the medial aspect of the calf contralateral to the surgical side. Ibuprofen and acetaminophen were given for 2 days before the first burn injury and again from the time of surgery. In the controls, the two burn injuries were separated by 7 days. Sensory variables included cumulated pain score during induction of the burn (visual analog scale), secondary hyperalgesia area, and mechanical and thermal pain perception and pain thresholds assessed before and 1 h after the burn injury. RESULTS: The heat injuries induced significant increases in pain perception (P < 0.001) and decreases in pain thresholds (P < 0.02). Baseline heat pain thresholds were higher during the second burn injury in patients (P < 0.001) and controls (P < 0.01). However, there were no significant differences in pain to heat injury (P > 0.8), secondary hyperalgesia areas (P > 0.1), mechanical and thermal pain perception (P > 0.1), or mechanical and thermal pain thresholds (P > 0.08) in the burn area before surgery compared to after surgery. CONCLUSION: Arthroscopic knee surgery did not modify nociceptive responses to a contralaterally applied experimental burn injury.     

Effects of potassium channel-blocking agents on spontaneous discharges from neuromas in rats

Thirty-five Sprague-Dawley rats with saphenous neuromas underwent acute microfilament recording in the proximal nerve. The effect of the potassium channel-blocking agents, tetraethylammonium bromide (TEA) and 4-aminopyridine, on spontaneous activity in A fibers terminating in the neuroma was observed. The effects of gallamine were also tested. Of the two channel-blocking agents, TEA reliably increased spontaneous firing in active fibers and initiated spontaneous activity in some fibers with no spontaneous baseline discharge. 4-Aminopyridine had no effect on baseline activity of either spontaneously active or quiescent fibers: however, it inhibited spontaneous activity induced by prior TEA treatment. Gallamine application produced effects similar to TEA in that spontaneous activity was dramatically increased. These results imply that a tonic potassium conductance is present in regenerating fibers in the neuroma and that this conductance moderates the tendency toward hyperexcitability and spontaneous firing. Spontaneous activity in nociceptive afferent fibers may represent the mechanism of chronic pain and paresthesias that often accompany peripheral nerve injury. These results suggest that agents which either increase potassium conductance or selectively inhibit the sodium current in regenerating axons might be effective in the treatment of these chronic pain syndromes.     

Different symptoms of neuropathic pain can be induced by different degrees of compressive force on the C7 dorsal root of rats

Background contextNeuropathic pain after nerve injuries is characterized by positive and negative sensory symptoms and signs. The extent of sensory fiber loss after nerve injuries has been demonstrated to correlate with symptoms of neuropathic pain by quantitative sensory testing and confirmed by biopsies of small nerve fibers. However, the relationship between the pathologic changes of large nerves on injuries and resulting pain symptoms remains unclear.PurposeTo investigate the relationship between the extent of dorsal root injury and resulting symptoms of neuropathic pain.Study designNerve injury and assessment of the following pain-related behaviors and neuropathologic changes.MethodsA total of 24 adult male Sprague-Dawley rats weighing 250 to 300 g were randomly divided into three groups (n=8 each): sham group operated on but without nerve compression, 70 gf group, and 180 gf group; a compression force of 70 or 180 g was applied to the right C7 dorsal root, separately. Threshold thermal and mechanical pains were measured before surgery (baseline) and on the first, third, fifth, and seventh day after surgery. On the seventh day after surgery, all rats were killed, and the structural alterations of nerve fibers within the compressed areas were examined.ResultsA compression force of 70 g resulted in hyperalgesia, whereas a compression force of 180 g induced hypoalgesia in the ipsilateral forepaw in response to both mechanical and thermal stimulations within 7 days after injury. Light microscopy and electron microscopy revealed a mild to moderate sensory fiber loss after 70-gf compression and a more severe sensory fiber loss after 180-gf compression.ConclusionsTransient injuries on sensory fibers can produce either positive or negative symptoms of neuropathic pain, and the different extent of sensory fiber loss after different degrees of injuries might account for the varied resulting symptoms of neuropathic pain.     

Memory of pain: the effect of perineural resiniferatoxin

The long-lasting imprint of acute pain in the central nervous system may contribute to the transition of acute pain to chronicity. The long-term potentiation (which is proposed as a mechanism of memory) and central sensitization were each reported as a form of synaptic plasticity, and both can be initiated by stimulation of C fibers. In the current study, we assessed nociceptive memory regarding hyperalgesia by measuring distant hyperalgesia after repeated carrageenan-induced inflammation. This approach was used to determine whether selective blockade of C fibers can prevent the development of a long-lasting imprint of hyperalgesia. In rat experiments, resiniferatoxin was administered percutaneously at the sciatic and saphenous nerves, and two crossover intraplantar injections of carrageenan into the hindpaws were performed 2 wk apart. Responses to noxious pressure and heat and changes in paw volumes were measured at various intervals during two carrageenan-induced inflammations. The experiments demonstrated that after recovery of hyperalgesia induced by the initial inflammation, repeated inflammation led to the development of a distant hyperalgesia that was absent during the initial inflammation. The maximum of distant hyperalgesia (decrease of noxious pressure threshold in the contralateral hindpaw from 141 +/- 23 g to 96 +/- 19 g; P < 0.0001) was reached 24 h after the second injection of carrageenan. The development of distant hyperalgesia during the repeated inflammation was completely prevented (P < 0.0002) by perineural resiniferatoxin (0.001%) administered before the initial injection of carrageenan. These results indicate that selective blockade of nociceptive fibers prevents formation of long-term hyperalgesia-related imprint in the central nervous system. Thus, pain memory can be preempted by selective and prolonged blockade of C-fibers.     

Effect of administration of antibodies against nerve growth factor in a rat model of muscle injury

IntroductionAlthough muscle injury is a common source of pain, the mechanism causing such pain is not completely known. We have previously reported nerve growth factor (NGF) as a proinflammatory mediator involved in acute pain, and clinical trials have shown the effectiveness of anti-NGF antibodies for management of low back pain. Here, we aim to examine the effects of anti-NGF antibodies on muscle-derived pain by studying their effects on sensory innervation in a rat muscle injury model.MethodsA nervous system tracer, Fluoro-Gold, was applied to both gastrocnemius muscles of 24 male Sprague Dawley rats to stain the sensory nerves. Then, the drop-mass method was used to damage the right gastrocnemius muscle of the posterior limb. Anti-NGF antibodies (50 μL) were injected into the injured muscles in 12 rats. Tissues were evaluated 1, 3, and 7 days post-injury by performing haematoxylin-and-eosin (HE) staining. The percentage of the total number of FG-positive cells that were also positive for a pain-related neuropeptide, calcitonin gene-related peptide (CGRP), was determined for the bilateral dorsal root ganglia from L1 to L6 7 days post-injury.ResultsHE staining showed active inflammation, indicated by increased basophil and eosinophil accumulation, at the injury site 1 and 3 days post-injury, as well as scar tissue formation 7 days post-injury. Injection of anti-NGF reduced muscle necrosis 1 and 3 days post-injury, and resulted in replacement of granulation tissue and muscle fibre regeneration 7 days post-injury. Anti-NGF also significantly inhibited CGRP among FG-positive cells (treatment group 38.2%, control group 49.6%; P < 0.05).DiscussionThis study found active inflammation induced by NGF, which may contribute to pain after muscle injury. Anti-NGF antibodies successfully suppressed the pain mediator NGF and inhibited inflammation, suggesting NGF as a target for control in pain management.     

Stereospecific effect of pregabalin on ectopic afferent discharges and neuropathic pain induced by sciatic nerve ligation in rats.

BACKGROUND: The new anticonvulsants, gabapentin and pregabalin, are effective in the treatment of neuropathic pain. The sites and mechanisms of their analgesic action are not fully known. The authors have previously demonstrated that systemic gabapentin suppresses ectopic afferent discharges recorded from injured sciatic nerves in rats. In the current study, they further examined the stereospecific effect of pregabalin on neuropathic pain and afferent ectopic discharges in a rodent model of neuropathic pain. METHODS: Tactile allodynia and thermal hyperalgesia were induced by partial ligation of the left sciatic nerve in rats. Single-unit activity of afferent ectopic discharges was recorded from the sciatic nerve proximal to the site of ligation. RESULTS: Intravenous injection of 10-30 mg/kg pregabalin dose-dependently attenuated tactile allodynia (n = 10) and thermal hyperalgesia (n = 8). The stereoisomer of pregabalin, R-3-isobutylgaba, had no analgesic effect in this dose range. Furthermore, intravenous injection of pregabalin, but not R-3-isobutylgaba, significantly inhibited the ectopic discharges from injured afferents in a dose-dependent manner (from 20.8 +/- 2.4 impulses/s during control to 2.3 +/- 0.7 impulses/s after treatment with 30 mg/kg pregabalin, n = 15). Pregabalin did not affect the conduction velocity of afferent fibers and the response of normal afferent nerves to mechanical stimulation. CONCLUSIONS: These data strongly suggest that the analgesic effect of pregabalin on neuropathic pain is likely mediated, at least in part, by its peripheral inhibitory action on the impulse generation of ectopic discharges caused by nerve injury.     

Stereospecific Effect of Pregabalin on Ectopic Afferent Discharges and Neuropathic Pain Induced by Sciatic Nerve Ligation in Rats

Background : The new anticonvulsants, gabapentin and pregabalin, are effective in the treatment of neuropathic pain. The sites and mechanisms of their analgesic action are not fully known. The authors have previously demonstrated that systemic gabapentin suppresses ectopic afferent discharges recorded from injured sciatic nerves in rats. In the current study, they further examined the stereospecific effect of pregabalin on neuropathic pain and afferent ectopic discharges in a rodent model of neuropathic pain.

Methods : Tactile allodynia and thermal hyperalgesia were induced by partial ligation of the left sciatic nerve in rats. Single-unit activity of afferent ectopic discharges was recorded from the sciatic nerve proximal to the site of ligation.

Results : Intravenous injection of 10-30 mg/kg pregabalin dose-dependently attenuated tactile allodynia (n = 10) and thermal hyperalgesia (n = 8). The stereoisomer of pregabalin, R-3-isobutylgaba, had no analgesic effect in this dose range. Furthermore, intravenous injection of pregabalin, but not R-3-isobutylgaba, significantly inhibited the ectopic discharges from injured afferents in a dose-dependent manner (from 20.8 +/- 2.4 impulses/s during control to 2.3 +/- 0.7 impulses/s after treatment with 30 mg/kg pregabalin, n = 15). Pregabalin did not affect the conduction velocity of afferent fibers and the response of normal afferent nerves to mechanical stimulation.