鞘内注射P物质拮抗氯胺酮的抗伤害作用

目的观察脊髓P物质对氯胺酮抗伤害作用的影响。方法在小鼠福尔马林实验中,结合行为学和Fos蛋白表达,观察鞘内注射(it)不同剂量的P物质对氯胺酮抗伤害作用的影响。结果氯胺酮20、30mg·kg-1ip可剂量依赖性地减少小鼠舔足时间(P<0.05)。P物质0.25、0.5ngit可增加注射氯胺酮小鼠舔足时间(P<0.05)。小鼠注射福尔马林后,注射侧脊髓背角Fos免疫样(Foslikeimmunoreactive,FLI)阳性神经元数量明显增加(P<0.01),预先给于氯胺酮30mg.kg-1ip可以明显减少脊髓背角FLI阳性神经元数量(P<0.01),而P物质0.5ngit能明显削弱氯胺酮对脊髓背角Fos表达的抑制(P<0.01)。结论鞘内注射P物质能拮抗脊髓水平氯胺酮抗伤害作用。     

鞘内注射6-羟多巴胺、α_1受体拮抗剂对氯胺酮脊髓镇痛作用的影响

目的　在体探讨脊髓去甲肾上腺素 (NE)能神经元α1受体和氯胺酮 (Ket)脊髓镇痛的关系。方法　用热水甩尾法观察鞘内注射 (ith)氯胺酮 5 0、10 0、2 0 0 μg对小鼠甩尾潜伏期(TFL)的影响。并观察鞘内分别预先注射 6 羟多巴胺 (6 OH DA ,6 μg)、α1受体拮抗剂哌唑嗪 (Pra,5、15 μg)或特拉唑嗪(Ter,5、15 μg )对Ket(10 0 μg ,ith)脊髓镇痛的影响。 结果　Ket(5 0 μg ,ith)对小鼠TFL无影响 (P >0 0 5 ) ,而Ket(10 0、2 0 0μg ,ith)可剂量依赖性地延长小鼠TFL(P <0 0 5 )。鞘内单独注射 6 OHDA、Pra或Ter对小鼠的痛阈无影响 (P >0 0 5 )。ith 5 μgPra或Ter对Ket脊髓镇痛无影响 (P >0 0 5 ) ,而ith 6 OHDA、15 μgPra或Ter则可明显减弱Ket脊髓镇痛 (P <0 0 5 )。结论　脊髓是Ket的镇痛部位之一 ,Ket脊髓镇痛和脊髓NE神经元α1受体有关     

鞘内注射纳洛酮对小剂量丙泊酚抗内脏伤害作用的影响

目的研究丙泊酚内脏痛镇痛机制是否与脊髓阿片受体有关。方法56只成年雄性SD大鼠蛛网膜下腔埋入导管后随机均分为8组，分别鞘内预注生理盐水（NS）或纳洛酮2μg／只、4μg／只或8μg／只，再腹腔注射NS或丙泊酚10mg／kg，随后采用结直肠扩张的内脏痛实验动物模型，以腹壁明显收缩变平的最小扩张压力值作为内脏痛反应（VMR）阈值，观察大鼠60min内内脏痛阈的变化。结果单纯腹腔注射小剂量丙泊酚后，5～25min内大鼠内脏痛阈显著升高（P〈0．01），10min达高峰（％MPE=37．2％）；单纯鞘内预注不同剂量纳洛酮大鼠内脏痛阈无明显变化（P〉0．05）；先鞘内预注不同剂量纳洛酮再腹腔注射丙泊酚后，丙泊酚所致抗内脏伤害作用被不同程度的减弱。结论（1）小剂量丙泊酚对内脏伤害刺激具有抑制作用；（2）纳洛酮剂量依赖、时间依赖地拮抗丙泊酚的抗内脏伤害作用，其作用机制与脊髓阿片受体有关。     

大鼠鞘内注射AP5的抗内脏伤害作用

目的观察鞘内注射竞争性N-甲基-D-天冬氨酸（NMDA）受体拮抗剂2-氨基-5-磷酰基戊酸酯（AP5）对大鼠结直肠扩张（CRD）诱发的内脏伤害性刺激的影响及剂量关系。方法利用大鼠CRD模型诱导的内脏伤害性刺激,经鞘内引入药物,观察对腹壁撤回反射（AWR）达到3级时痛阈的影响。结果AP5剂量依赖地抑制CRD诱导的内脏伤害性刺激,并有时间作用特点。结论竞争性NMDA受体拮抗剂AP5可以抑制CRD诱导的内脏伤害性刺激,NMDA受体在内脏伤害性刺激脊髓水平的传递中起重要作用。     

鞘内注射荷包牡丹碱和L-烯丙基甘氨酸对氯胺酮脊髓镇痛的影响

目的　在体研究脊髓GABAA 受体和氯胺酮(Ket)脊髓镇痛的关系 ,并初步探讨突触前、后机制在其中的作用。方法　用热水甩尾法和醋酸扭体法 ,观察鞘内注射 (ith)Ket(2 5 ,5 0 ,10 0 μg)对小鼠痛阈的影响。并用热水甩尾法观察GABAA 受体拮抗剂荷包牡丹碱 (Bic ,0 .0 5 ,0 .1,0 .2 μg ,ith) ,GABA合成酶抑制剂L 烯丙基甘氨酸 (AG ,2 0 0mg·kg- 1,ip)及两药合用对小鼠基础痛阈和Ket(10 0 μg ,ith)脊髓镇痛的影响。结果　Ket可产生剂量依赖性的镇痛作用。Bicith对小鼠痛阈无明显影响 ,但可明显减弱Ket的脊髓镇痛作用。ipAG或合用Bic(0 .0 5 ,0 .1μg,ith)对小鼠痛阈都无明显影响 ,而预先AGip可明显减弱Ket脊髓镇痛作用 ;且AGip后 ,Bic(0 .1μg ,ith)对Ket脊髓镇痛无明显拮抗作用。 结论　脊髓是Ket的镇痛部位之一 ,Ket的镇痛作用可能和Ket促进脊髓释放GABA有关。     

一氧化氮与抗伤害作用的研究进展

一氧化氮（ＮＯ）作为一种新型信使分子，具有独特的生物化学和生物物理性质。近年来发现ＮＯ与痛觉传导密切相关，ＮＯ分子可致痛，也可增加人和动物对疼痛的敏感性，在动物的伤害实验中，抑制ＮＯ的生成具有明显的抗伤害作用。本文对ＮＯ的生成、调节和抑制ＮＯ生成所产生的抗伤害作用进行了综述。     

异丙酚对氯胺酮所致大脑皮质神经元损害保护作用的机制

目的:观察异丙酚对氯胺酮诱导的cfos基因在大鼠大脑后扣带回皮质区表达的影响,并探讨异丙酚预防或减轻氯胺酮所致精神症状及神经损害的机制。方法:雄性Wistar大鼠30只,随机分为生理盐水5ml组、氯胺酮100mg·kg-1组、异丙酚100mg·kg-1组、异丙酚50mg·kg-1 氯胺酮100mg·kg-1组、异丙酚100mg·kg-1 氯胺酮100mg·kg-1组。异丙酚与氯胺酮用药间隔15min。所用药物用生理盐水配至5ml经腹腔注射。各组动物于用药后2h,断头处死,分离脑组织,用半定量RTPCR技术和免疫组织化学方法检测各组cfosmRNA与cfos蛋白在大鼠后扣带回皮质区表达的变化。结果:氯胺酮可明显诱导cfosmRNA与cfos蛋白在大鼠后扣带回皮质区的表达;异丙酚自身不能诱导cfosmRNA和cfos蛋白的表达;预先给予异丙酚可显著抑制氯胺酮诱导的cfosmRNA和cfos蛋白在这一区域的表达,且抑制效应成剂量依赖性。结论:异丙酚可抑制氯胺酮诱导的cfosmRNA与cfos蛋白在大脑后扣带回皮质区的表达,这可能是其预防或减轻氯胺酮所致精神症状和神经损害的机制之一。     

可乐定局部应用的抗伤害作用

目的 探讨局部应用可乐定的抗伤害反应作用及其耐受性的产生。方法 观察了局部应用可乐定的抗伤害效应、药物处理时间与可乐定抗伤害效应间的关系、提前全身给予纳洛酮或育亨宾对可乐定抗伤害效应的影响及局部应用氯胺酮对可乐定抗伤害耐受发生的影响。结果 在药物局部处理过的小鼠尾部，可乐定产生了浓度相关性的抗伤害效应；局部应用可乐定的抗伤害效应的强度与局部暴露于药液的时间相关；育亨宾完全阻断了可乐定的抗伤害作用，纳洛酮则无明显影响；氯胺酮与可乐定同时局部给药对可乐定抗伤害耐受的产生没有影响。结论 局部应用可乐定可通过激活外周的 α2肾上腺素能受体产生浓度依赖性的抗伤害效应，避免了全身给药的副作用；反复给药能产生抗伤害耐受，局部应用氯胺酮未能阻止这种耐受的发生，说明外周NMDA受体没有参与耐受的发生。     

鞘内注射p-MPPF对异氟烷镇痛作用的影响

目的探讨异氟烷(isoflurane,Iso)镇痛作用与小鼠脊髓5-HT1A受体的关系。方法昆明种小鼠腹腔注射Iso建立镇痛模型。分别以甩尾法、热板法、醋酸扭体法(15min内)评估小鼠鞘内注射5-HT1A受体拮抗剂p-MPPF(6μg和3μg)对Iso镇痛作用的影响。结果单独鞘内注射p-MPPF对小鼠甩尾潜伏期、热板痛阈、扭体次数无影响(P>0.05)。与Iso镇痛组(Iso组)相比,合用药组(Iso+M6组,Iso+M3组)甩尾潜伏期与热板痛阈均缩短(P<0.01或P<0.05);Iso+M6组扭体次数较Iso组增多(P<0.05),Iso+M3组无变化(P>0.05)。结论 Iso体表镇痛作用与激动小鼠脊髓5-HT1A受体密切相关。     

GABA_A受体对鞘内注射氧化槐定碱镇痛作用的影响

观察氧化槐定碱(oxysophoridine,OSR)鞘内注射(intrathecal injection,ith)的镇痛作用并探讨与GABAA受体相关的作用机制。采用小鼠温浴法测定痛阈,观察OSR(ith)的镇痛作用及GABAA受体激动剂和拮抗剂对OSR镇痛作用的影响;采用免疫组化法检测OSR对小鼠脊髓背角GABAARα1蛋白表达的影响。结果显示,OSR(12.5和6.25 mg·kg-1,ith)能明显延长热甩尾潜伏期(P<0.05,P<0.01),痛阈提高率达68.45%。GABA和蝇蕈醇(MUS)与OSR有协同镇痛作用,印防己毒素(PTX)和荷包牡丹碱(BIC)能拮抗OSR的镇痛作用。OSR(12.5 mg·kg-1,ith)可使脊髓背角GABAARα1表达明显增多(P<0.01)。结果提示,OSR(ith)具有明显的镇痛作用,脊髓GABAA受体参与了OSR的镇痛机制。     

Effects of intrathecal 6-hydroxydopamine, α1 and α2 adrenergic receptor antagonists on antinociception of propofol in mice

AIM: To investigate the relationship between spinal cord norepinephrine, alpha1 and alpha2 adrenergic receptors and antinociception of propofol in mice. METHODS: Kunming mice were used. Antinociceptive tests were investigated with the tail-immersion test and the acetic acid-induced writhing test. The effects of subcutaneous (sc), intrathecal (ith) and intracerebroventricular (icv) injection propofol on pain threshold were observed. The influences of pretreatment with ith 6-hydroxydopamine, alpha1R antagonist prazosin, or alpha2R antagonist yohimbine on the antinociception of propofol were studied. RESULTS: Significant antinociception was produced by propofol (25, 50 mg/kg, sc) and propofol (20, 40 microg, ith) in tail-immersion test and acetic the acid-induced writhing test (P<0.05 or P<0.01). Icv propofol (10, 20, and 40 microg) did not produce any effect on pain threshold in mice (P>0.05). The 6-hydroxydopamine (5 and 10 microg), prazosin (5 and 10 microg), or yohimbine (5 and 10 microg) ith alone did not affect basal tail-flick latency (TFL) in conscious mice, but significantly reduced the TFL as measured by tail-immersion test in propofol (50 mg/kg, sc)-treated mice, compared with basal TFL and vehicle groups (P<0.05 or P<0.01). CONCLUSION: The spinal cord is a target of propofol antinociception. In mice propofol antinociception is partly mediated by spinal norepinephrine, alpha1R and alpha2R.     

鞘内注射士的宁对丙泊酚镇痛作用的影响

目的　探讨脊髓甘氨酸受体与丙泊酚镇痛作用的关系。方法　以热板法和扭体法测小鼠痛阈的变化 ,观察鞘内注射 (it)不同剂量士的宁对丙泊酚小鼠痛阈的影响。结果　丙泊酚 12 5mg·kg-1腹腔注射 (ip)对小鼠热板法痛阈 (painthresholdinhot platetest,HPPT)无影响 (P >0 0 5 ) ,2 5、5 0mg·kg-1可使小鼠HPPT增加 (P <0 0 5 ) ;丙泊酚 5mg·kg-1静脉注射 (iv)对小鼠扭体次数无影响 (P >0 0 5 ) ,7 5、10mg·kg-1iv可使小鼠扭体次数减少 (P <0 0 5 )。士的宁0 2 5 μgit对丙泊酚小鼠 (5 0mg·kg-1,ip)HPPT无影响 (P>0 0 5 ) ;0 5、0 75、1 0 μgit均可减少丙泊酚小鼠的HPPT(P <0 0 5 )。士的宁 0 2 5、0 5、0 75、1 0 μgit对丙泊酚小鼠 (10mg·kg-1,iv)扭体次数均无影响 (P >0 0 5 )。结论　丙泊酚在热板法和扭体法中产生不同的镇痛作用 ,前者可能与脊髓甘氨酸受体有关 ,后者与脊髓甘氨酸受体关系不大     

Effects of intrathecal NMDA and AMPA receptors agonists or antagonists on antinociception of propofol

AIM: To study the effects of intrathecal (it) agonists and antagonists of N-methyl-D-aspartate (NMDA) and alpha amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors and NMDAR1 antisense oligodeoxynucleotides (AS ODN) on the antinociception of propofol. METHODS: Hot-plate test (HPPT) and acetic acid-induced writhing test were used to measure the nociceptive thresholds in mice. The effects of intrathecal NMDA,     

鞘内注射GABA转运体-1抑制剂NO-711对神经病理痛大鼠脊髓Fos蛋白表达的影响

目的:观察脊髓水平GABA转运体-1(γ-aminobutyric acid transporter-1,GAT-1)抑制剂NO-711对坐骨神经慢性松结扎(chronic constriction injury,CCI)大鼠机械痛敏和热痛敏以及Fos蛋白表达的影响,探讨NO-711抗伤害性的可能机制。方法:雄性SD大鼠84只,随机分为4组(n=21):假手术生理盐水组、假手术抑制剂组、神经损伤生理盐水组和神经损伤抑制剂组。各组大鼠CCI前5 d进行鞘内置管,在术前测定基础机械性缩足反射阈值(mechanical withdrawal threshold,MWT)和热缩足潜伏期(thermal withdrawal laten-cy,TWL)及Fos蛋白的表达,CCI后5 d鞘内注射100μg NO-711或生理盐水,测定节扎前、给药前、给药后0.5,1,2,4和8 h大鼠MWL和TWL及Fos蛋白的表达。结果:与给药前和神经损伤生理盐水组相比,神经损伤抑制剂组大鼠在给药后机械痛敏和热痛敏以及Fos蛋白的表达均逐渐降低,并随时间的延长又逐渐恢复到给药前水平,在给药后1 h时作用最明显,并一直持续到给药后4 h...     

Studies with ketamine and alfentanil following Freund's complete adjuvant-induced inflammation in rats

1. N-Methyl-D-aspartate (NMDA) receptor antagonists suppress inflammatory hyperalgesia and the development of acute opioid tolerance. They may also enhance opioid-induced antinociception, while suppressing postopioid-induced hyperalgesia and opioid-enhanced inflammatory hyperalgesia. 2. The non-competitive NMDA receptor antagonist, ketamine, is a racemic chiral drug; its individual enantiomers have differing affinities for the NMDA receptor. The anaesthetic and antinociceptive potencies of (S)-ketamine are 1.5- and threefold higher, respectively, than those of (R)-ketamine in laboratory rodents. 3. The present study investigated the effects of racemic ketamine and enantiopure (S)-ketamine on inflammatory hyperalgesia in rats, 5 days after intraplantar injection of Freund's complete adjuvant (FCA) into one hind paw. First, racemic or (S)-ketamine was administered alone; second, racemic or (S)-ketamine was administered 30 min after initiation of i.v. infusions of the micro-opioid agonist, alfentanil. 4. Area under the curve (AUC) values for Von Frey paw withdrawal threshold (PWT) versus time curves were significantly increased (P < 0.05) for both inflamed and non-inflamed hind paws by racemic and (S)-ketamine (5 & 10 mg/kg, s.c.). Similarly, AUC values for reduction of hind paw volume versus time were significantly increased (P < 0.05) by racemic and (S)-ketamine (10 mg/kg, s.c.). 5. Alfentanil infusions significantly increased PWT in both hind paws, but neither racemic nor (S)-ketamine (5 mg/kg, s.c.) administered 30 min after initiation of alfentanil infusion produced further increases in PWT. 6. Racemic and (S)-ketamine produced antinociceptive effects in both hind paws, but an antihyperalgesic effect per se was not apparent. Additionally, there was a possible anti-inflammatory effect of both drugs in the inflamed hind paw. These findings complement previous studies in which non-competitive NMDA receptor antagonists suppressed behavioural hyperalgesia. 7. However, racemic and (S)-ketamine did not further enhance alfentanil's antinociceptive effects, although they appeared to prolong alfentanil's antinociceptive effects in the non-inflamed hind paw. These findings suggest that factors such as time-course, frequency and the mode of administration of NMDA receptor antagonists, in addition to the type of antinociceptive model (i.e. inflammatory compared with acute) and the nociceptive testing procedure (i.e. noxious mechanical compared with low threshold stimuli) may influence their effects on opioid-induced antinociception.     

Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind-up of the second pain response in healthy male volunteers

AIMS: The aim of this study was to assess the efficacy of dextromethorphan and ketamine relative to placebo on the acute nociceptive threshold and wind-up of second pain response in healthy male volunteers. METHODS: The trial was a randomized, double-blind, placebo-controlled, three period crossover, double dummy design in 12 healthy male volunteers. During each of the three periods (which were separated by a 1 week washout period) each volunteer received either a single oral dose of 0.7 mg kg(-1) dextromethorphan and placebo to ketamine, or placebo to dextromethorphan followed by a single intravenous injection of 0.375 mg kg(-1) ketamine, or placebo to both dextromethorphan and ketamine. The trial did not schedule administration of both ketamine and dextromethorphan together. Acute nociceptive thresholds and wind-up of second pain were measured in the skin of the thenar eminence of the ventral surfaces of the right and left hands, using a SOMEDIC thermotest apparatus, before and at the estimated tmax for dextromethorphan (i.e. 2.15 h). Blood pressure and heart rate were also monitored before dosing and after the dosing regimen. RESULTS: Neither dextromethorphan nor ketamine had any significant effect on acute nociceptive thresholds on either hand (P>0.05). Moreover, dextromethorphan was without any significant effect (P>0.05) on the wind-up of the second pain response on either hand. The lsmean number of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 15.84 vs 16.48 (-5.52, 4.24) and 11.75 vs 15.25 (-11.89, 4.90) for left- and right-hand, respectively, following dextromethorphan administration. In contrast ketamine produced significant reductions in wind-up to second pain in both the left and right hands (P=0.0002 and 0.0386, respectively). The lsmean numbers of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 28.41 vs 16.48 (6.60, 17.25) and 25.00 vs 15.25 (0.58, 18.93) for left- and right-hand, respectively. CONCLUSIONS: Wind-up of second pain induced by noxious heat is sensitive to intervention by ketamine, which is known to block the NMDA receptor. These data infer that the wind-up phenomenon evoked by noxious heat involves the activation of NMDA receptors. This volunteer model of pain may have utility in the evaluation of agents that modulate their antinociceptive actions via NMDA mechanisms.     

Effect of ketamine pretreatment on cocaine-mediated hepatotoxicity in rats

Cocaine (COC) produces hepatotoxicity by a mechanism, which remains undefined, but has been linked to its oxidative metabolism. Ketamine (KET) is also a potentially hepatotoxic agent. The abuse of KET with COC is currently popular among young abusers therefore; this study was conducted to investigate the possible potentiation of COC-mediated hepatotoxicity (CMH) by KET. Male Sprague Dawley (SD) rats were administered oral KET hydrochloride for three consecutive days at a dose of 100 mg/kg with and without a single dose of COC (5 mg/kg, i.v.) administered 18 h after the last KET dose. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured as markers of liver injury. Liver reduced glutathione (GSH) levels were determined as well as the activities of glutathione peroxidase (GPx) and catalase (CAT). In addition, the activity of liver glutathione reductase (GRx) was measured. The results demonstrate that KET pretreatment potentiated the hepatotoxicity of COC. Serum ALT and AST were significantly elevated with the combined KET and COC treatment versus all other treatments. While COC alone resulted in focal inflammatory cell infiltration, COC administration after KET pretreatment produced sub-massive hepatic necrosis. Hepatic GSH content was significantly reduced in KET-pretreated COC group compared to the other treatment groups, rendering the liver more susceptible to oxidative stress. Moreover, there was a significant decrease in the activities of hepatic GPx and CAT, particularly with the KET-pretreated COC group. In addition, norcocaine (NC) was only detected in the plasma of rats received COC after KET pretreatment. In conclusion, this study demonstrates that KET pretreatment potentiates the hepatotoxicity of COC as revealed by an array of biochemical and morphological markers most probably due to increase in COC oxidative metabolism.     

氯胺酮对大鼠头端延髓腹外侧区前交感神经元的作用(英文)

目的:研究氯胺酮在中枢交感心血管活动中的调节作用。方法:在25只氨基甲酸乙酯麻醉、三碘季铵酚制动并人工通气的雄性SD大鼠中,共细胞外记录到32个头端延髓腹外侧区前交感神经元的自发放电,这些神经元具有压力敏感性和向脊髓投射的特点。观察选择性NMDA受体拮抗剂氯胺酮对前交感神经元放电的影响。结果:静脉注射不同剂量的氯胺酮(3,6,12mg/kg)能增加RVLM前交感神经元的放电频率,同时能阻断这些神经元的压力敏感性,且具有剂量依赖性的特点。结论:氯胺酮通过阻断RVLM前交感神经元压力感受反射的紧张性抑制,从而调节交感心血管活动。     

Effect of diabetes on the mechanisms of intrathecal antinociception of sildenafil in rats

The mechanism of intrathecal antinociceptive action of the phosphodiesterase 5 inhibitor sildenafil was assessed in diabetic rats using the formalin test. Intrathecal administration of sildenafil (12.5-50 microg) produced a dose-related antinociception during both phases of the formalin test in non-diabetic and diabetic rats. Intrathecal pretreatment with N-L-nitro-arginine methyl ester (L-NAME, nitric oxide (NO) synthase inhibitor, 1-50 microg), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor, 1-10 microg), KT5823 (protein kinase G (PKG) inhibitor, 5-500 ng), charybdotoxin (large-conductance Ca2+-activated K+ channel blocker, 0.01-1 ng), apamin (small-conductance Ca2+-activated K+ channel blocker, 0.1-3 ng) and glibenclamide (ATP-sensitive K+ channel blocker, 12.5-50 microg), but not N-D-nitro-arginine methyl ester (D-NAME, 50 microg) or saline, significantly diminished sildenafil (50 microg)-induced antinociception in non-diabetic rats. Intrathecal administration of ODQ, KT5823, apamin and glibenclamide, but not L-NAME nor charybdotoxin, reversed intrathecal antinociception induced by sildenafil in diabetic rats. Results suggest that sildenafil produces its intrathecal antinociceptive effect via activation of NO-cyclic GMP-PKG-K+ channels pathway in non-diabetic rats. Data suggest that diabetes leads to a dysfunction in NO and large-conductance Ca2+-activated K+ channels. Sildenafil could have a role in the pharmacotherapy of diabetes-associated pain.