The effect of heat conditioning of the primary area before and after induction of hyperalgesia by topical/intradermal capsaicin or by controlled heat injury

The aim of the present study was to test the effect of heat conditioning before and after the induction of hyperalgesia. Three different methods were used for induction of hyperalgesia, topical capsaicin, intradermal capsaicin injection, and a controlled heat injury. The vascular (blood flow and skin temperature) and sensory changes (area of secondary hyperalgesia and ongoing pain) associated with the cutaneous hyperalgesia were compared. Each experiment consisted of two randomized sessions separated by at least 2 days. In one session, pre-conditioning of the skin by heat was performed 30 min before the induction of hyperalgesia using a probe at 45°C for 5 min in the center of the expected primary hyperalgesic area. After the induction of hyperalgesia, heat conditioning was performed twice in the center of the primary hyperalgesic area using a temperature of 2°C above the present individual pain threshold. On the contra-lateral arm, no heat conditioning was applied while hyperalgesia was induced using the same method. This session was evaluated as a control. The preconditioning induced an increased skin temperature in the primary area for both topical capsaicin and the controlled heat injury. Postconditioning caused increased blood flow in the secondary hyperalgesic area for the topical capsaicin method and increased blood flow in the primary hyperalgesic area for the controlled heat injury method. However, conditioning with heat in an attempt to increase the C-fiber input did not have any effect on the ongoing pain ratings and sensory test results in any of the methods. The results of the present study suggest that there is still a need for a better experimental model with more stable allodynia both between sessions and between subjects while at the same time minimizing discomfort to the volunteer.     

Attenuation of experimental pruritus and mechanically evoked dysesthesiae in an area of cutaneous allodynia

We investigated the effects of tactile allodynia on the itch and mechanically evoked dysesthesiae produced by an intradermal injection of histamine in human volunteers. After an intradermal injection of capsaicin into the volar surface of one forearm, there developed an area of tactile allodynia to stroking and hyperalgesia to pricking the skin. Histamine was then injected simultaneously into the area of allodynia (experimental arm) and into the opposite forearm (control arm). Magnitude estimates of itch were obtained every 15 s for 5 min, and the areas of cutaneous hyperalgesia (pricking-evoked pain), alloknesis (stroking-evoked itch), hyperknesis (pricking-evoked itch) and wheal and flare were measured. The areas of wheal and flare were not significantly different on the two arms. The magnitude of itch and the areas of hyperknesis and alloknesis developed normally on the control arm but were absent or greatly reduced on the experimental arm. Thus, both the itch and the alloknesis and hyperknesis normally induced by histamine were absent or greatly reduced when histamine was injected in an area of capsaicin-induced allodynia. These results are compatible with the hypothesis that activity in capsaicin-sensitive, nociceptive primary afferent neurons evokes a central neuronal inhibitory process that prevents or reduces the itch and mechanically evoked dysesthesiae normally produced by an intradermal injection of histamine.     

Secondary heat hyperalgesia detected by radiant heat stimuli in humans: evaluation of stimulus intensity and duration

Diverging observations on secondary hyperalgesia to heat stimuli have been reported in the literature. No studies have investigated the importance of heat stimulus intensity and duration for the assessment of secondary heat hyperalgesia. The present study was designed to investigate systematically (1) if pain sensitivity to radiant heat stimuli (focused Xenon light) is altered in the area of secondary punctuate hyperalgesia induced by intradermal injection of capsaicin and (2) if heat stimulus duration and intensity had an influence on the ability to detect secondary heat hyperalgesia.Pain ratings to radiant heat stimuli from a focused xenon lamp were assessed within the area of secondary punctuate hyperalgesia in fifteen volunteers before and after intradermal injection of capsaicin. The stimulus conditions were systematically varied between three intensity levels (0.8, 1.0 and 1.2 x heat pain threshold (PT)) and four duration steps (200, 350, 500 and 750 ms). The present study shows that long duration (350-750 ms) and low intensity (0.8 and 1.0 x PT) radiant heat stimuli were adequate to detect secondary heat hyperalgesia.     

Secondary heat hyperalgesia detected by radiant heat stimuli in humans: Evaluation of stimulus intensity and duration

Diverging observations on secondary hyperalgesia to heat stimuli have been reported in the literature. No studies have investigated the importance of heat stimulus intensity and duration for the assessment of secondary heat hyperalgesia. The present study was designed to investigate systematically (1) if pain sensitivity to radiant heat stimuli (focused Xenon light) is altered in the area of secondary punctuate hyperalgesia induced by intradermal injection of capsaicin and (2) if heat stimulus duration and intensity had an influence on the ability to detect secondary heat hyperalgesia.

Pain ratings to radiant heat stimuli from a focused xenon lamp were assessed within the area of secondary punctuate hyperalgesia in fifteen volunteers before and after intradermal injection of capsaicin. The stimulus conditions were systematically varied between three intensity levels (0.8, 1.0 and 1.2?×?heat pain threshold (PT)) and four duration steps (200, 350, 500 and 750?ms). The present study shows that long duration (350–750?ms) and low intensity (0.8 and 1.0 ×?PT) radiant heat stimuli were adequate to detect secondary heat hyperalgesia.     

Anesthesiologists' practice patterns for treatment of postoperative nausea and vomiting in the ambulatory Post Anesthesia Care Unit

Background

Induction of the COX-2 isoenzyme appears to play a major role in the genesis of central sensitization after nociceptive stimulation. This study aimed to investigate the efficacy of a single, oral dose of the specific COX-2 inhibitor-valdecoxib in attenuating the central sensitization – induced secondary hyperalgesia in a heat/capsaicin pain model in healthy volunteers.

Methods

The study was a randomized, double blind, placebo controlled, crossover, single dose efficacy trial using 20 healthy volunteers. Two hours following placebo or 40 mg, PO valdecoxib, participants underwent skin sensitization with heat/capsaicin, as well as supra-threshold pain and re-kindling measurements according to an established, validated pain model. Subjects rated pain intensity and unpleasantness on a visual analog scale and the area of secondary hyperalgesia was serially mapped.

Results

The area of secondary hyperalgesia produced after 40 mg of valdecoxib was no different than that after placebo. Furthermore, there were no significantly relevant differences when volunteers were treated with valdecoxib or placebo in relation to either cold- or hot pain threshold or the intensity of pain after supra-threshold, thermal pain stimulation.

Conclusion

We demonstrated that a single, oral dose of valdecoxib when does not attenuate secondary hyperalgesia induced by heat/capsaicin in a cutaneous sensitization pain model in healthy volunteers.     

Localization of Chemical Stimulation: Capsaicin on Hairy Skin

The ability to localize a chemical stimulus applied to the skin of the forearm was compared to the ability to localize a punctate tactile stimulus. The chemical stimulus was a single, 6-μ1 drop of a 1.0% solution of capsaicin in an ethanol vehicle; the tactile stimulus was a polyester monofilament that exerted 7.5 g of force. Subjects attempted to localize the stimuli at 30-sec intervals for a period of 13.5 min, and rated the perceived intensity and quality of the chemogenic sensations. To avoid generating potentially confounding tactile sensations, localization attempts were made by pointing to the area of sensation with a focused light beam. The results showed that overall, chemical localization was inferior to tactile localization: The absolute error of localization averaged 2.5 cm for capsaicin compared to 1.4 cm for the monofilament. The experiment also revealed that chemical localization (1) varied significantly across arms, (2) exhibited a relatively strong bias toward the elbow, and (3) appeared to be unaffected by the perceived intensity of the sensation. The dominant sensation quality reported was itch. The results are discussed in the context of cutaneous localization in general and localization in the nociceptive system in particular.     

Pain assessment following experimental maxillofacial surgical procedure in sheep

The aim of this study was to investigate the severity and duration of postoperative pain and hyperalgesia in sheep undergoing mandibular reconstructive surgery. Stimulus-evoked sensitivity at the surgical site and an area remote from injury, the ipsilateral and contralateral forelimbs, was measured as objective indicators of altered pain processing in adult female sheep (n = 7). Responses were recorded before surgery and one, two, three, seven and 14 days afterwards. Concentrations of the acute-phase protein haptoglobin were measured in serum as a marker of inflammation before and at one and seven days after surgery. A significant decrease in forelimb mechanical withdrawal thresholds (secondary hyperalgesia) and response thresholds to punctate stimulation of the area surrounding the surgical incision (allodynia) was detected one day after surgery and persisted for at least three days, despite intra- and postoperative analgesic treatment. Concentrations of haptoglobin were significantly increased one day post-surgery, indicating the presence of a significant acute inflammatory response, and returned to pre-surgical concentrations by seven days. These data provide a deeper insight into understanding the impact of surgery in experimental animals, and may assist in formulating more effective analgesic and antihyperalgesic treatment regimens postoperatively.     

Oral irritation by mustard oil: self-desensitization and cross-desensitization with capsaicin

We investigated the temporal pattern of oral irritation elicited by sequential application of mustard oil (allyl-isothiocyanate), and whether it exhibits self-desensitization and cross-desensitization with capsaicin. Mustard oil (0.125%, 40 micro l) was sequentially applied to one side of the tongue at 1 min intervals, and subjects rated the intensity of the irritant sensation elicited by each stimulus. Ratings successively declined across trials, indicating desensitization. In contrast, sequential application of capsaicin (10 ppm) elicited irritation that increased in intensity across trials (sensitization). To test for self-desensitization by mustard oil, a 10 min hiatus was imposed following the series of unilateral mustard oil stimuli, after which mustard oil was applied to both sides of the tongue. In a two-alternative forced-choice paradigm, subjects chose which side had stronger irritation and also independently rated the irritant intensity on each side. A significant majority of subjects chose the side not previously receiving mustard oil as more intense, and assigned significantly higher intensity ratings to that side, indicating self-desensitization. In two additional sessions, the same paradigm was used to show mustard oil cross-desensitization of irritation elicited by capsaicin, and capsaicin cross-desensitization of irritation from mustard oil. In a final session, sequential application of mustard oil at faster (20 s) intervals initially evoked a sensitizing pattern followed by desensitization. The temporal patterns of oral irritation exhibited by mustard oil, and its reciprocal cross-desensitization with capsaicin, are similar to those of menthol and nicotine.     

Altered nociceptive behavior and emotional contagion of pain in mouse models of autism

Individuals with autism spectrum disorder (ASD) have altered sensory processing but may ineffectively communicate their experiences. Here, we used a battery of nociceptive behavioral tests to assess sensory alterations in two commonly used mouse models of ASD, BTBR T⁺Itpr3^tf/J (BTBR), and fragile-X mental retardation-1 knockout (Fmr1-KO) mice. We also asked whether emotional contagion, a primitive form of empathy, was altered in BTBR and Fmr1 KO mice when experiencing pain with a social partner. BTBR mice demonstrated mixed nociceptive responses with hyporesponsivity to mechanical/thermal stimuli and intraplantar injections of formalin and capsaicin while displaying hypersensitivity on the acetic acid test. Fmr1-KO mice were hyposensitive to mechanical stimuli and intraplantar injections of capsaicin and formalin. BTBR and Fmr1-KO mice developed significantly less mechanical allodynia following intraplantar injections of complete Freund's adjuvant, while BTBR mice developed slightly more thermal hyperalgesia. Finally, as measured by the formalin and acetic acid writhing tests, BTBR and Fmr1-KO mice did not show emotional contagion of pain. In sum, our findings indicate that depending on the sensation, pain responses may be mixed, which reflects findings in ASD individuals.     

Sensory properties of citric acid: psychophysical evidence for sensitization, self-desensitization, cross-desensitization and cross-stimulus-induced recovery following capsaicin

In a first experiment, human subjects used a bipolar scale to rate the irritant sensation elicited by 10 sequentially repeated applications of either 3 ppm capsaicin or 250 mM citric acid on one side of the dorsal surface of the tongue, at 1 min intervals (30 s inter-stimulus interval). Citric acid-evoked irritation significantly increased across trials, consistent with sensitization. With capsaicin there was a large degree of inter- and intra-individual variation in successive ratings with no overall sensitization. Following the sequential stimulation series and a 10 min rest period, self- and cross-desensitization effects were tested in a two-alternative forced choice (2-AFC) paradigm by placing either citric acid or capsaicin on both sides of the tongue and asking subjects to indicate which side of the tongue yielded a stronger irritant sensation. Subjects also gave separate intensity ratings for irritation on each side of the tongue. Capsaicin self-desensitization was confirmed, while cross-desensitization to citric acid was not observed. In addition, citric acid self-desensitization and cross-desensitization to capsaicin were observed. In a second experiment a stronger capsaicin solution (33 ppm) was applied to one side of the tongue using cotton swabs. After the burning sensation elicited by capsaicin had disappeared, citric acid was applied bilaterally and cross-desensitization was observed using the same 2-AFC and rating procedures. This was followed by repeated re-application of citric acid at 1 min intervals to the capsaicin-treated side. The irritant sensation elicited by citric acid increased significantly, indicating a 'cross-stimulus-induced recovery' from capsaicin desensitization. In a final experiment we investigated the effect of the sodium channel blocker amiloride on the perceived irritation elicited by citric acid or capsaicin. Following application of amiloride to one side of the tongue with cotton swabs, either citric acid or capsaicin was applied bilaterally and subjects asked to perform a 2-AFC and intensity ratings. Amiloride significantly, albeit weakly, reduced the irritation elicited by citric acid while it weakly but significantly enhanced capsaicin-evoked irritation. These findings are discussed in terms of involvement of vanilloid and acid-sensitive ion channels in acid-evoked irritation and pain.     

Paclitaxel-induced neuropathic hypersensitivity in mice: responses in 10 inbred mouse strains

Mechanical allodynia, or hypersensitivity to tactile stimuli, is a frequent clinical symptom of neuropathy. Large interindividual differences have been observed in neuropathic pain, both in susceptibility to its development and in its severity. Identification of genetic factors relevant to this variability would be of obvious utility. Although many animal models of neuropathic pain following peripheral nerve injury have been developed, most involve intricate surgeries and are thus poorly suited for large-scale linkage mapping investigations in the mouse. Recently, a schedule of intraperitoneal injections of the chemotherapeutic agent, paclitaxel (Taxol(R)), has been shown to produce a long-lasting, bilateral neuropathy in the rat, featuring hypersensitivity to mechanical, thermal and cold stimuli. We present here a survey of the responses of 10 inbred mouse strains to paclitaxel injections. Virtually all strains developed statistically significant mechanical allodynia, with one strain, DBA/2J, exhibiting especially robust changes. Strain sensitivities to paclitaxel-induced mechanical allodynia were similar to those obtained previously using a surgical model of neuropathic pain, supporting our contention that genetic sensitivity to mechanical allodynia is independent of the precise mode of induction. Using sensitive DBA/2 mice and a resistant strain, C57BL/6J, for comparison, we further characterized the paclitaxel model in mice by examining cold allodynia and thermal hyperalgesia. Both strains displayed equivalent cold allodynia but neither strain developed thermal hyperalgesia. The present data confirm a genetic component in mechanical allodynia using this model, while dissociating mechanical hypersensitivity from other pain modalities.     

Time course of self-desensitization of oral irritation by nicotine and capsaicin

Nicotine contacting mucous membranes elicits irritation that decreases with repeated exposures (self-desensitization). We investigated the time course of nicotine self-desensitization and compared it with that of capsaicin. Nicotine (300 mM, 10 microl) was applied to one-half of the dorsal tongue and vehicle to the other. Following a rest period ranging from 0.5 to 48 h, nicotine (5 microl) was reapplied to each side of the tongue and subjects indicated on which side they experienced stronger irritation and separately rated the intensity of the sensation on each side. After intervals of 0.5, 1, and 24 h, a significant majority of subjects chose the vehicle-treated side as having stronger irritation and assigned significantly higher intensity ratings to that side, indicating self-desensitization. The effect was not present after 48 h. By comparison, 10 parts per million (ppm) (33 microM) capsaicin induced significant self-desensitization at 1 but not 24 h, whereas a higher concentration of capsaicin (100 ppm, 330 microM) induced significant self-desensitization at intervals of 1, 24, and 48 h. These results indicate that initial exposure to nicotine or capsaicin can markedly attenuate irritant sensations elicited by subsequent exposure to these irritants hours to days later.     

Comparison of the antinociceptive effects of ibuprofen arginate and ibuprofen in rat models of inflammatory and neuropathic pain

AimsIbuprofen arginate is a highly soluble salt formed by combining racemic ibuprofen with the amino acid l-arginine. This formulation is absorbed faster, and it is safe and effective in treating many forms of mild to moderate pain. We compared the analgesic effect of ibuprofen arginate and conventional ibuprofen in rat models of pain.Main methodsMechanical and cold allodynia were assessed in the chronic constriction injury (CCI) model of neuropathic pain, and mechanical allodynia was also examined in capsaicin-injected rats (a model of central sensitization). Inflammatory hypersensitivity was assessed with the formalin test. Ibuprofen-l-arginine, ibuprofen, l-arginine or saline was administered orally on a daily basis after CCI or capsaicin injection, and the von Frey and cold plate tests were performed on days 1, 3 and 7 after CCI or capsaicin administration. In the formalin-induced inflammatory pain test, the drugs were administered 30 min before formalin injection.Key findingsIbuprofen only exerts an antinociceptive effect in the formalin model whereas ibuprofen-l-arginine exerts antinociceptive effects on both mechanical and cold allodynia induced by CCI, mechanical allodynia induced by capsaicin injection, and in phase 2 of the formalin test, exhibiting superior antinociceptive activity to ibuprofen in all these tests. l-Arginine only exerted antinociceptive effects on cold allodynia in CCI.SignificanceThese results demonstrate that ibuprofen arginate has stronger antinociceptive effects than ibuprofen in all the models used, suggesting it might improve the therapeutic management of neuropathic and inflammatory pain.     

Effects of (1DMe)NPYF, a synthetic neuropeptide FF analogue, in different pain models.

The antinociceptive effects of intrathecal (IT) (1DMe)NPYF were studied in adult Sprague-Dawley rats. (1DMe)NPYF produced dose-dependent antinociception that was reduced by subcutaneous injection of naloxone. (1DMe)NPYF (0.5 nmol) also potentiated the antinociceptive effects of intrathecal morphine 7.8 nmol. This suggests that the antinociceptive effects of (1DMe)NPYF are partially mediated by opioid receptor activation. In carrageenan inflammation, 5-10 nmol of (1DMe)NPYF was effective against both thermal hyperalgesia and mechanical allodynia. In the neuropathic pain model, the lowest dose tested (0.5 nmol) showed antiallodynic effects against cold allodynia. The results suggest a potential role for (1DMe)NPYF in the treatment of pain including neuropathic pain.     

A Novel and Selective Poly (ADP-Ribose) Polymerase Inhibitor Ameliorates Chemotherapy-Induced Painful Neuropathy

Background

Chemotherapy-induced neuropathy is the principle dose limiting factor requiring discontinuation of many chemotherapeutic agents, including cisplatin and oxaliplatin. About 30 to 40% of patients receiving chemotherapy develop pain and sensory changes. Given that poly (ADP-ribose) polymerase (PARP) inhibition has been shown to provide neuroprotection, the current study was developed to test whether the novel PARP inhibitor compound 4a (analog of ABT-888) would attenuate pain in cisplatin and oxaliplatin-induced neuropathy in mice.

Results

An established chemotherapy-induced painful neuropathy model of two weekly cycles of 10 intraperitoneal (i.p.) injections separated by 5 days rest was used to examine the therapeutic potential of the PARP inhibitor compound 4a. Behavioral testing using von Frey, paw radiant heat, cold plate, and exploratory behaviors were taken at baseline, and followed by testing at 3, 6, and 8 weeks from the beginning of drug treatment.

Conclusion

Cisplatin-treated mice developed heat hyperalgesia and mechanical allodynia while oxaliplatin-treated mice exhibited cold hyperalgesia and mechanical allodynia. Co-administration of 50 mg/kg or 25 mg/kg compound 4a with platinum regimen, attenuated cisplatin-induced heat hyperalgesia and mechanical allodynia in a dose dependent manner. Similarly, co-administration of 50 mg/kg compound 4a attenuated oxaliplatin-induced cold hyperalgesia and mechanical allodynia. These data indicate that administration of a novel PARP inhibitor may have important applications as a therapeutic agent for human chemotherapy-induced painful neuropathy.     

Effects of Prostaglandin E2 and Capsaicin on Behavior and Cerebrospinal Fluid Amino Acid Concentrations of Unanesthetized Rats: A Microdialysis Study

Abstract: Prostaglandin E₂ (PGE₂) delivered to the spinal cord produces an increased sensitivity to noxious (hyperalgesia) and innocuous (allodynia) stimuli. The mechanisms that underlie this effect remain unknown, but a PGE₂-evoked enhancement of spinal neurotransmitter release may be involved. To address this hypothesis, we examined the effect of PGE₂ on CSF concentrations of amino acids and also the modulatory effect of PGE₂ on capsaicin-evoked changes of spinal amino acid concentrations using a microdialysis probe placed in the lumbar subarachnoid space. Amino acids were quantified using HPLC with fluorescence detection. Addition of 1 mM, but not 10 or 100 µM, PGE₂ to the perfusate for a 10-min period (flow rate, 5 µl/min) evoked an immediate increase (80–100%) in glutamate (Glu), aspartate (Asp), taurine (Tau), glycine (Gly), and γ-aminobutyric acid (GABA) concentrations. Similarly, capsaicin infusion (0.1–10 µM) induced a dose-dependent increase in Glu, Asp, Tau, Gly, GABA, and ethanolamine levels. Significant increases in amino acid levels evoked by PGE₂ or capsaicin were associated with a touch-evoked allodynia. The combination of PGE₂ (10 µM) and capsaicin (0.1 or 1.0 µM) at concentrations that individually had no effect together evoked a significant increase (60–100%) in Glu, Asp, Tau, Gly, and GABA concentrations and produced tactile allodynia. These data demonstrate that spinally delivered PGE₂ or capsaicin substantially elevates CSF concentrations of both excitatory and inhibitory amino acids. The capacity of PGE₂ to enhance and prolong capsaicin-evoked amino acid concentrations may be one of the mechanisms by which spinal PGE₂ produces hyperalgesia and allodynia.     

Intrathecal CART (55-102) attenuates hyperlagesia and allodynia in a mouse model of neuropathic but not inflammatory pain

CART peptides are found in brain and spinal cord areas involved in pain transmission. In the present study, we investigated the role of rat CART (55-102) in the modulation of chronic pain using models of chronic neuropathic (nerve injury model) and inflammatory (carrageenan test) pain models in the mouse after intrathecal administration. The results show that CART (55-102) was highly effective in reversing the hyperalgesia and allodynia signs of chronic neuropathic pain in a dose-related manner at doses (0.05-2 microg/mouse) that did not affect motor coordination of the animals. These effects lasted for at least 3 h after injection and were not blocked by naloxone, an opiate antagonist. Although CART (55-102) attenuated carrageenan-induced hyperalgesia, it failed to reduce the inflammation associated with this model. These results suggest the involvement of the CART peptides in the development of hyperalgesia and allodynia associated with neuropathic pain.     

急性神经损伤引起脊髓背角C-纤维诱发电位长时程增强

神经损伤引起神经病性疼痛,表现为持续性痛超敏和痛觉过敏。目前对神经病性疼痛的机制尚缺乏了解。我们以往的工作表明强直电刺激坐骨神经可引起脊髓背角C-纤维诱发电位的长时程增强(long-term potentiation,LTP),该LTP被认为是病理性疼痛的突触模型。本研究的目的在于探讨急性神经损伤是否能在完整动物的脊髓背角诱发出C-纤维诱发电位LTP。在以测试刺激(10～20V,0．5ms)电刺激坐骨神经的同时在脊髓背角用微电极记录C一纤维诱发电位。分别用强直刺激、剪断或夹捏坐骨神经诱导LTP。结果发现：(1)剪断或夹捏坐骨神经都可以诱导脊髓背角C-纤维诱发电位的LTP,该LTP可持续到实验结束(3～9h),在剪断神经前10min用利多卡因局部阻滞坐骨神经则可完全阻断LTP的产生;(2)神经损伤诱导的LTP可被NMDA受体阻断剂AP5所阻断;(3)用单次强直刺激引起LTP后,切断坐骨神经可使LTP的幅度进一步增大,而用多次强直电刺激使LTP饱和后,损伤神经则不能使LTP进一步增大。切断神经引起LTP后,强直电刺激也不能使LTP进一步增大。这些结果表明,急性神经损伤可以诱导脊髓背角C纤维诱发电位LTP,且切断神经能更有效地诱导LTP。该试验进一步支持我们的设想,即脊髓背角C-纤维诱发电位LTP可能在病理性疼痛的形成中起重要作用。     

Cerebrospinal fluid beta-endorphin in models of hyperalgesia in the rat

Cerebrospinal fluid (CSF) obtained by acute percutaneous puncture of the cisternal membrane of the halothane anesthetized rat has low but measurable concentrations of beta-endorphin-like immunoreactivity (beta-EPir: 32.8 +/- 3.0 pmol/l). Chromatographic separation of beta-EPir showed that authentic beta-endorphin1-31 was the main component of beta-EPir in cisternal CSF. Subcutaneous injection of 5% formalin in the hind paws did not increase beta-EPir in cisternal CSF. Rats with tactile paw hyperalgesia evoked by unilateral ligation of the L5/6 nerve roots 2 weeks earlier had beta-EPir concentrations that did not differ from sham operated or unoperated control animals. In contrast, capsaicin injected in the hindpaws increased the mean beta-EPir concentration compared to saline injections (P = 0.006) 45 min after emerging from anesthesia following injection. These results show that acute activation of C fibers (by capsaicin) will evoke the release of beta-endorphin into the CSF, suggesting activation of the beta-endorphin terminal systems in the brain/midbrain. The failure of formalin injections to release beta-EPir to CSF may be due to specificity of the afferent stimulus evoking beta-EPir release, a lower stimulus intensity, and/or the duration of the stimulus generated by formalin. The normal concentrations of beta-EPir found in the hyperalgesic state following nerve injury suggest that the supraspinal beta-endorphin system does not display tonic changes under such conditions.     

Evaluation of Anti-Hyperalgesic and Analgesic Effects of Two Benzodiazepines in Human Experimental Pain: A Randomized Placebo-Controlled Study

Background and Aims

Compounds that act on GABA-receptors produce anti-hyperalgesia in animal models, but little is known on their effects in humans. The aim of this study was to explore the potential usefulness of GABA-agonism for the control of pain in humans. Two agonists at the benzodiazepine-binding site of GABA_A-receptors (clobazam and clonazepam) were studied using multiple experimental pain tests. Positive results would support further investigation of GABA agonism for the control of clinical pain.

Methods

In a randomized double-blind crossover design, 16 healthy male volunteers received clobazam 20 mg, clonazepam 1 mg and tolterodine 1 mg (active placebo). The area of static hyperalgesia after intradermal capsaicin injection was the primary endpoint. Secondary endpoints were: area of dynamic hyperalgesia, response to von Frey hair stimulation, pressure pain thresholds, conditioned pain modulation, cutaneous and intramuscular electrical pain thresholds (1, 5 and 20 repeated stimulation), and pain during cuff algometry.

Results

For the primary endpoint, an increase in the area of static hyperalgesia was observed after administration of placebo (p<0.001), but not after clobazam and clonazepam. Results suggestive for an anti-hyperalgesic effect of the benzodiazepines were obtained with all three intramuscular pain models and with cuff algometry. No effect could be detected with the other pain models employed.

Conclusions

Collectively, the results are suggestive for a possible anti-hyperalgesic effect of drugs acting at the GABA_A-receptors in humans, particularly in models of secondary hyperalgesia and deep pain. The findings are not conclusive, but support further clinical research on pain modulation by GABAergic drugs. Because of the partial results, future research should focus on compounds acting selectively on subunits of the GABA complex, which may allow the achievement of higher receptor occupancy than unselective drugs. Our data also provide information on the most suitable experimental models for future investigation of GABAergic compounds.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01011036","term_id":"NCT01011036"}}NCT01011036