Chronic Constriction Injury of the Distal Infraorbital Nerve (DIoN-CCI) in Mice to Study Trigeminal Neuropathic Pain.

Animal models remain necessary tools to study neuropathic pain. This manuscript describes the distal infraorbital nerve chronic constriction injury (DIoN-CCI) model to study trigeminal neuropathic pain in mice. This includes the surgical procedures to perform the chronic constriction injury and the postoperative behavioral tests to evaluate the changes in spontaneous and evoked behavior that are signs of ongoing pain and mechanical allodynia. The methods and behavioral readouts are similar to the infraorbital nerve chronic constriction injury (IoN-CCI) model in rats. However, important changes are necessary for the adaptation of the IoN-CCI model to mice. First, the intra-orbital approach is replaced by a more rostral approach with an incision between the eye and the whisker pad. The IoN is thus ligated distally outside the orbital cavity. Secondly, due to the higher locomotor activity in mice, allowing rats to move freely in small cages is replaced by placing mice in custom-designed and constructed restraining devices. After DIoN ligation, mice exhibit changes in spontaneous behavior and in response to von Frey hair stimulation that are similar to those in IoN-CCI rats, i.e., increased directed face grooming and hyperresponsiveness to von Frey hair stimulation of the IoN territory.

Antagonism of Transient Receptor Potential Ankyrin Type-1 Channels as a Potential Target for the Treatment of Trigeminal Neuropathic Pain: Study in an Animal Model.

Transient receptor potential ankyrin type-1 (TRPA1) channels are known to actively participate in different pain conditions, including trigeminal neuropathic pain, whose clinical treatment is still unsatisfactory. The aim of this study was to evaluate the involvement of TRPA1 channels by means of the antagonist ADM_12 in trigeminal neuropathic pain, in order to identify possible therapeutic targets. A single treatment of ADM_12 in rats 4 weeks after the chronic constriction injury of the infraorbital nerve (IoN-CCI) significantly reduced the mechanical allodynia induced in the IoN-CCI rats. Additionally, ADM_12 was able to abolish the increased levels of TRPA1, calcitonin gene-related peptide (CGRP), substance P (SP), and cytokines gene expression in trigeminal ganglia, cervical spinal cord, and medulla induced in the IoN-CCI rats. By contrast, no significant differences between groups were seen as regards CGRP and SP protein expression in the pars caudalis of the spinal nucleus of the trigeminal nerve. ADM_12 also reduced TRP vanilloid type-1 (TRPV1) gene expression in the same areas after IoN-CCI. Our findings show the involvement of both TRPA1 and TRPV1 channels in trigeminal neuropathic pain, and in particular, in trigeminal mechanical allodynia. Furthermore, they provide grounds for the use of ADM_12 in the treatment of trigeminal neuropathic pain.

Functional respiratory imaging after neostigmine- or sugammadex-enhanced recovery from neuromuscular blockade in the anesthetised rat: a randomised controlled pilot study / Imagem funcional da respiração após aceleração da recuperação do bloqueio neuromuscular com neostigmina ou sugamadex em ratos anestesiados: estudo piloto controlado e randomizado

Abstract Objectives Reductions in diaphragm activity are associated with the postoperative development of atelectasis. Neostigmine reversal is also associated with increased atelectasis. We assessed the effects of neostigmine, sugammadex, and spontaneous reversal on regional lung ventilation and airway flow. Methods Six Sprague-Dawley rats were paralysed with rocuronium and mechanically ventilated until recovery of the train-of-four ratio to 0.5. We administered neostigmine (0.06 mg.kg-1), sugammadex (15 mg.kg-1), or saline (n = 2 per group). Computed tomography scans were obtained during the breathing cycle. Three-dimensional models of lung lobes were generated using functional respiratory imaging technology, and lobar volumes were calculated during the breathing cycle. The diaphragmatic surface was segmented for the end-expiratory and end-inspiratory scans. The total change in volume was reported by the lung volume change from the end-expiratory scan to the end-inspiratory scan. Chest wall movement was defined as the lung volume change minus the volume change that resulted from diaphragm excursion. Results The two rats that received neostigmine exhibited a smaller relative contribution of diaphragm movement to the total change in lung volume compared with the two rats that received sugammadex or saline (chest wall contribution (%): 26.69 and 25.55 for neostigmine; -2.77 and 15.98 for sugammadex; 18.82 and 10.30 for saline). Conclusion This pilot study in rats demonstrated an increased relative contribution of chest wall expansion after neostigmine compared with sugammadex or saline. This smaller relative contribution of diaphragm movement may be explained by a neostigmine-induced decrease in phrenic nerve activity or by remaining occupied acetylcholine receptors after neostigmine.

Resumo Objetivos As reduções da atividade do diafragma estão associadas ao desenvolvimento de atelectasia no período pós-operatório. A reversão com neostigmina também está associada ao aumento de atelectasia. Avaliamos os efeitos de neostigmina, sugamadex e da reversão espontânea sobre a ventilação pulmonar regional e o fluxo aéreo. Métodos Seis ratos Sprague-Dawley foram paralisados com rocurônio e mecanicamente ventilados até a recuperação da sequência de quatro estímulos atingir relação 0,5. Administramos neostigmina (0,06 mg.kg-1), sugamadex (15 mg.kg-1) ou solução salina (n = 2 por grupo). As tomografias foram feitas durante o ciclo respiratório. Modelos tridimensionais dos lobos pulmonares foram gerados com a tecnologia de imagem funcional respiratória e os volumes lobares foram calculados durante o ciclo respiratório. A superfície diafragmática foi segmentada para as varreduras expiratória final e inspiratória final. A alteração total no volume foi relatada pela alteração do volume pulmonar da varredura expiratória final para a varredura inspiratória final. O movimento da parede torácica foi definido como a variação do volume pulmonar menos a alteração no volume resultante da excursão do diafragma. Resultados Os dois ratos que receberam neostigmina apresentaram uma contribuição relativa menor do movimento do diafragma para a alteração total do volume pulmonar em comparação com os dois ratos que receberam sugamadex ou solução salina (contribuição da parede torácica (%): 26,69 e 25,55 para neostigmina; -2,77 e 15,98 para sugamadex; 18,82 e 10,30 para solução salina). Conclusão Este estudo piloto com ratos demonstrou uma contribuição relativa aumentada de expansão da parede torácica após neostigmina em comparação com sugamadex ou solução salina. Essa contribuição relativa menor de movimento do diafragma pode ser explicada por uma redução induzida por neostigmina na atividade do nervo frênico ou por receptores de acetilcolina permanecerem ocupados após a administração de neostigmina.

[Functional respiratory imaging after neostigmine- or sugammadex-enhanced recovery from neuromuscular blockade in the anesthetised rat: a randomised controlled pilot study]. / Imagem funcional da respiração após aceleração da recuperação do bloqueio neuromuscular com neostigmina ou sugamadex em ratos anestesiados: estudo piloto controlado e randomizado.

OBJECTIVES: Reductions in diaphragm activity are associated with the postoperative development of atelectasis. Neostigmine reversal is also associated with increased atelectasis. We assessed the effects of neostigmine, sugammadex, and spontaneous reversal on regional lung ventilation and airway flow. METHODS: Six Sprague-Dawley rats were paralysed with rocuronium and mechanically ventilated until recovery of the train-of-four ratio to 0.5. We administered neostigmine (0.06mg.kg-1), sugammadex (15mg.kg-1), or saline (n=2 per group). Computed tomography scans were obtained during the breathing cycle. Three-dimensional models of lung lobes were generated using functional respiratory imaging technology, and lobar volumes were calculated during the breathing cycle. The diaphragmatic surface was segmented for the end-expiratory and end-inspiratory scans. The total change in volume was reported by the lung volume change from the end-expiratory scan to the end-inspiratory scan. Chest wall movement was defined as the lung volume change minus the volume change that resulted from diaphragm excursion. RESULTS: The two rats that received neostigmine exhibited a smaller relative contribution of diaphragm movement to the total change in lung volume compared with the two rats that received sugammadex or saline (chest wall contribution (%): 26.69 and 25.55 for neostigmine; -2.77 and 15.98 for sugammadex; 18.82 and 10.30 for saline). CONCLUSION: This pilot study in rats demonstrated an increased relative contribution of chest wall expansion after neostigmine compared with sugammadex or saline. This smaller relative contribution of diaphragm movement may be explained by a neostigmine-induced decrease in phrenic nerve activity or by remaining occupied acetylcholine receptors after neostigmine.

The selective sigma-1 receptor antagonist E-52862 attenuates neuropathic pain of different aetiology in rats.

E-52862 is a selective σ1R antagonist currently undergoing phase II clinical trials for neuropathic pain and represents a potential first-in-class analgesic. Here, we investigated the effect of single and repeated administration of E-52862 on different pain-related behaviours in several neuropathic pain models in rats: mechanical allodynia in cephalic (trigeminal) neuropathic pain following chronic constriction injury of the infraorbital nerve (IoN), mechanical hyperalgesia in streptozotocin (STZ)-induced diabetic polyneuropathy, and cold allodynia in oxaliplatin (OX)-induced polyneuropathy. Mechanical hypersensitivity induced after IoN surgery or STZ administration was reduced by acute treatment with E-52862 and morphine, but not by pregabalin. In the OX model, single administration of E-52862 reversed the hypersensitivity to cold stimuli similarly to 100 mg/kg of gabapentin. Interestingly, repeated E-52862 administration twice daily over 7 days did not induce pharmacodynamic tolerance but an increased antinociceptive effect in all three models. Additionally, as shown in the STZ and OX models, repeated daily treatment with E-52862 attenuated baseline pain behaviours, which supports a sustained modifying effect on underlying pain-generating mechanisms. These preclinical findings support a role for σ1R in neuropathic pain and extend the potential for the use of selective σ1R antagonists (e.g., E-52862) to the chronic treatment of cephalic and extra-cephalic neuropathic pain.

Chronic Constriction Injury of the Rat's Infraorbital Nerve (IoN-CCI) to Study Trigeminal Neuropathic Pain.

Animal models are important tools to study the pathophysiology and pharmacology of neuropathic pain. This manuscript describes the surgical and behavioral procedures to study trigeminal neuropathic pain in rats. To meet the specificity of trigeminal neuropathic pain syndromes, the infraorbital nerve (IoN) is subjected to a chronic constriction injury (CCI) by loosely ligating the nerve. An intra-orbital approach is presented here to expose and ligate the IoN in the orbital cavity. After IoN ligation, rats exhibit changes in spontaneous behavior and in response to von Frey hair stimulation that are indicative of persistent pain and mechanical allodynia. Two phases can be defined in the development of the behavioral changes. During the first week following IoN-CCI (phase 1), rats show an increased and asymmetric face grooming activity, i.e., with face wash strokes primarily directed to the nerve-injured IoN territory. A distinction is made between face grooming behavior that is part of a more general body grooming behavior, which remains largely unaffected by IoN-CCI, and face grooming that is neither preceded nor followed by body grooming, which is significantly increased after IoN-CCI. During this period, responsiveness to mechanical stimulation of the IoN territory is reduced. This hyporesponsiveness is abruptly replaced by an extreme hyperresponsiveness whereby even very weak stimulus intensities provoke nocifensive behavior (phase 2). The phenomenological similarities between these behavioral alterations and reported signs of facial pain (i.e., responses to noxious stimulation of the face) suggest the presence of dysesthesia/paresthesia and mechanical allodynia in the ligated IoN territory.

Behavioral study of non-evoked orofacial pain following different types of infraorbital nerve injury in rats.

Directed isolated face grooming following unilateral chronic constriction injury to the infraorbital nerve (IoN-CCI) is a unique measure of spontaneous neuropathic pain. Variability between rats and the limited duration of the increased face grooming behavior has hampered its usefulness. We studied three possible sources of variability: variations in surgery, pre-existing differences in nocifensive behavior between the rats and variation in time. Three different types of IoN lesion were performed: loose ligation (CCI), tight ligation (CCI-T) and partial tight ligation (PTL, Seltzer method); the latter two offer greater surgical standardization. Face grooming behavior following IoN injury, on the one hand, and during the orofacial formalin test, on the other hand, was analyzed and correlated. Significant differences in isolated face grooming behavior were found between the IoN groups. Interestingly, CCI-T rats continued to show significantly increased isolated face grooming for the duration of the experiment, i.e., up to 32 days post-operative, whereas CCI animals were no longer significantly different from sham animals after two weeks. Surprisingly, PTL operated rats only showed minor effects. Variability was not smaller in the CCI-T or PTL group. Face grooming behavior after IoN lesion was poorly correlated to that in the orofacial formalin test. It is therefore unclear if pre-existing behavioral differences between animals are a major cause of variability in the IoN-CCI model. Finally, repeated testing showed significant variability in time. It is concluded that tight ligation of the IoN nerve has long-lasting effects on face grooming behavior and that part of the variability in face grooming behavior may be reduced by performing repeated testing.

Cerebral activation during von Frey filament stimulation in subjects with endothelin-1-induced mechanical hyperalgesia: a functional MRI study.

Endothelin-1 (ET-1) is an endogenously expressed potent peptide vasoconstrictor. There is growing evidence that ET-1 plays a role in the pain signaling system and triggers overt nociception in humans. The underlying neuronal pathways are still a matter of great debate. In the present study, we applied an intradermal ET-1 sensitization model to induce mechanical hyperalgesia in healthy subjects. Functional magnetic resonance imaging (fMRI) was used to tease out the cortical regions associated with the processing of ET-1-induced punctate hyperalgesia, as compared to a nonnoxious mechanical stimulation of the contralateral arm. Von Frey hair testing revealed the presence of increased responsiveness to punctate stimulation in all subjects. Activational patterns between nonpainful control stimulation and hyperalgesic stimulation were compared. Two major observations were made: (1) all cortical areas that showed activation during the control stimulation were also present during hyperalgesic stimulation, but in addition, some areas showed bilateral activation only during hyperalgesic stimulation, and (2) some brain areas showed significantly higher signal changes during hyperalgesic stimulation. Our findings suggest that injection of ET-1 leads to a state of punctate hyperalgesia, which in turn causes the activation of multiple brain regions. This indicates that ET-1 activates an extended neuronal pathway.

Altered sensitivity to mechanical stimulation during prolonged subcutaneous administration of endothelin-1 in rats.

Cancer pain is often difficult to treat. Growing evidence indicates that chemical mediators secreted by the tumor itself play an important role in the development of cancer pain. One such mediator, endothelin-1 (ET-1) is secreted by different tumor types. Studies have indicated that ET-1 induces spontaneous and evoked nociception in rodents and in humans. The focus of all these studies has always been on a single administration of ET-1. Such an acute exposure to ET-1 however bears little resemblance to the clinical condition in which cancer patients are exposed continuously for many months to increased levels of ET-1. To improve the knowledge of the pathological role of ET-1 in cancer, we developed an animal model of prolonged exposure to ET-1. Rats were exposed to subcutaneous administration of ET-1 for seven consecutive days, with a total amount of 67.4 nmol. On days +2, +3, +5, +7, and +10 sensitivity to von Frey hairs and to pin-prick stimulation were evaluated. Prolonged administration of ET-1 induced signs of mechanical allodynia on several time points. Although the administered doses were very small, prolonged administration of ET-1 seems to lead to a state of mechanical allodynia.

Endothelin-1-induced pain and hyperalgesia: a review of pathophysiology, clinical manifestations and future therapeutic options.

Pain in patients with metastatic cancer contributes to increased suffering in those already burdened by their advancing illness. The causes of this pain are unknown, but are likely to involve the action of tumour-associated mediators and their receptors. In recent years, several chemical mediators have increasingly come to the forefront in the pathophysiology of cancer pain. One such mediator, endothelin-1 (ET-1), is a peptide of 21 amino acids that was initially shown to be a potent vasoconstrictor. Extensive research has revealed that members of the ET family are indeed produced by several epithelial cancerous tumours, in which they act as autocrine and/or paracrine growth factors. Several preclinical and clinical studies of various malignancies have suggested that the ET axis may represent an interesting contributor to tumour progression. In addition, evidence is accumulating to suggest that ET-1 may contribute to pain states both in humans and in other animals. ET-1 both stimulates nociceptors and sensitises them to painful stimuli. Selective stimulation of ET receptors has been implicated as a cause of inflammatory, neuropathic and tumoural pain. ET-1-induced pain-related behaviour seems to be mediated either solely by one receptor type or via both endothelin-A receptors (ETAR) and endothelin-B receptors (ETBR). Whereas stimulation of ETAR on nociceptors always elicits a pain response, stimulation of ETBR may cause analgesia or elicit a pain response, depending on the conditions. The administration of ETAR antagonists in the receptive fields of these nociceptors has been shown to ameliorate pain-related behaviours in animals, as well as in some patients with advanced metastatic prostate cancer. The identification of tumour-associated mediators that might directly or indirectly cause pain in patients with metastatic disease, such as ET-1, should lead to improved, targeted analgesia for patients with advanced cancer. In this review, we will describe the current status of the role of ET-1 in different types of painful syndromes, with special emphasis on its role in the pathophysiology of cancer pain. Finally, potential new treatment options that are based on the role of the ET axis in the pathophysiology of cancer are elaborated.

Curative-like analgesia in a neuropathic pain model: parametric analysis of the dose and the duration of treatment with a high-efficacy 5-HT(1A) receptor agonist.

High-efficacy activation of central 5-HT(1A) receptors by means of the recently discovered, selective 5-HT(1A) receptor ligand, F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]methyl}piperidin-1-yl]methanone, fumaric acid salt] causes an unprecedented, broad-spectrum analgesia in rat models of acute and chronic pain of nociceptive and neuropathic origin; it also is effective in conditions where opioids either are ineffective, induce analgesic tolerance, or elicit persistent hyperalgesia/allodynia. Inversely mirroring morphine's actions, F 13640's ("curative-like") analgesic effects persist after the discontinuation of treatment. Here, we examined the relationships, if any, between the dose and the duration of F 13640 treatment on the one hand, and the duration of persistent analgesia on the other. Rats received unilateral infraorbital nerve injury and developed allodynia - as assessed by an increased response to von Frey filament stimulation - within 24 days; thereafter, using osmotic pumps, rats were subcutaneously infused with F 13640 in two experiments. In one, a one-week infusion was instituted at 0.04-10-mg/day doses; in a second experiment, a 0.63-mg/day dose was implemented for a duration ranging from 1 to 56 days. These 250- and 56-fold variations of the dose and duration of treatment caused post-treatment, persistent analgesia for about 10 and 40 days, respectively. At least as much as dose, the duration of F 13640 treatment determines F 13640-induced persistent analgesia. Neuroadaptive modulations at pre- and postsynaptic, brain and spinal cord 5-HT(1A) receptors may be involved in the dynamical, dose- and time-dependent, pre-treatment rise and post-treatment decay of the analgesia induced by high-efficacy 5-HT(1A) receptor activation.

Neurosensory changes in a human model of endothelin-1 induced pain: a behavioral study.

Although pain is a frequent feature in patients with cancer, its etiology is still poorly understood. In recent years, endothelin-1 (ET-1) has become a major target molecule in the etiology of cancer pain. In this randomised, double-blind study the effects of intradermal injection of ET-1 on spontaneous pain, temperature perception and sensation of punctate stimulation were evaluated. Thirty-five subjects were randomised to receive either placebo or one of four concentrations of ET-1 (ranging from 10(-10) to 10(-6)M). Besides assessment of spontaneous pain, three neurosensory testings were performed: (1) cold and warm sensation, (2) cold and heat pain, and (3) punctate stimulation using a von Frey monofilament. ET-1 produced a dose-dependent flare zone that was absent after placebo injection. Subjects reported a short-lasting spontaneous pain upon administration of the highest concentrations of ET-1. Injection of ET-1 induced a long-lasting and dose-dependent punctate hyperalgesia in an area around the injection site (secondary hyperalgesia). Thermal testing revealed a short period of hypoesthesia to non-noxious warm and cold stimuli after some doses of ET-1. In addition to the mechanical hyperalgesia, intradermal injection of ET-1 almost instantaneously induced a state of cold hyperalgesia outlasting the study period (120 min). No development of heat hyperalgesia was observed. The observed psychophysical characteristics of this new model of ET-1 induced nociception indicate its potential as a human experimental model for cancer pain.

High-efficacy 5-hydroxytryptamine 1A receptor activation counteracts opioid hyperallodynia and affective conditioning.

Pain may become intractable as tolerance develops to opioids and the opioids, paradoxically, induce pain. We examined the hypothesis that the analgesia produced by the novel analgesic and high-efficacy 5-hydroxytryptamine (5-HT)(1A) receptor agonist (3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]methyl]piperidin-1-yl]methanone, fumaric acid salt (F 13640) may counteract opioid-induced pain. In studies of the somatosensory quality of pain in infraorbital nerve-injured rats, morphine infusion (5 mg/day) by means of osmotic pumps initially caused analgesia (i.e., decreased the behavioral response to von Frey filament stimulation), followed by hyperallodynia and analgesic tolerance. Infusion of F 13640 (0.63 mg/day) prevented the development of opioid hyperallodynia and reversed opioid hyperallodynia once established. In studies of the affective/motivational quality of pain, F 13640 both prevented and reversed the conditioned place aversion induced by naloxone (0.04 mg/kg i.p.) in morphine-infused rats; F 13640 also prevented and reversed the conditioned place preference induced by morphine injections (7.5 mg/kg i.p.). The data confirm that opioids produce bidirectional hypo- and proalgesic actions, and offer initial evidence that high-efficacy 5-HT(1A) receptor activation counteracts both the sensory and the affective/motivational qualities of opioid-induced pain. The data also indicate that F 13640 may be effective with opioid-resistant pain. It further is suggested that opioid addiction may represent self-therapy of opioid-induced pathological pain.

Effects of the combined continuous administration of morphine and the high-efficacy 5-HT1A agonist, F 13640 in a rat model of trigeminal neuropathic pain.

F 13640 is a recently discovered high-efficacy 5-HT1A receptor agonist that has demonstrated robust anti-allodynic efficacy in a rat model of trigeminal neuropathic pain upon acute and continuous administration. In this model, continuous morphine infusion (5 mg/day) was shown to be effective during the first week of its administration but became almost completely ineffective by the end of the second week; F 13640's effectiveness (0.63 mg/day) remained unchanged during two weeks. Here, we examined the effects of combining F 13640 infusion with that of morphine. During the first week, the combination of the two agents produced a magnitude of effect that was similar to that of morphine when given alone and larger than that of F 13640 alone. During the second week, the combination produced an effect that was similar to that of F 13640 alone, and more effective than that of morphine alone. The latter data suggest that the 5-HT1A agonist, F 13640, inhibits the development of tolerance to morphine in this model. However, it is also possible that little, if any, interaction occurred between the different mechanisms initiated by opioid and 5-HT1A receptor activation, and that the anti-allodynic effect that remained by the end of the two-week treatment period is due solely to 5-HT1A receptor activation. The stable effects of F 13640 during the second week of treatment surpassed those of morphine and were not improved by the addition of morphine to F 13640.

Nonevoked facial pain in rats following infraorbital nerve injury: a parametric analysis.

Unilateral chronic constriction injury to the infraorbital nerve (IoN-CCI) induces an increase in face-grooming behavior that is not part of normal body grooming (i.e., "isolated face grooming"). Despite the validity of isolated face grooming as a measure of spontaneous neuropathic pain, variation between rats in postoperative face grooming has limited its usefulness. We examined whether performing bilateral rather than unilateral IoN surgery could induce a more stable face-grooming behavior. It was found that bilaterally ligated rats performed a significantly greater amount of isolated face grooming (approximately four- to fivefold) when compared with unilaterally ligated rats. However, this effect was accompanied by an equivalent increase in between-subjects variation. No significant difference in face grooming during body grooming was found between bilaterally and unilaterally ligated rats. Rats were observed in two different sizes of observation cages; also, in addition to the amount of time spent on face grooming, the number and average duration of the face-grooming episodes were recorded. The effects of IoN surgery are caused by increases in the number of episodes. The effects of cage size were mostly related to differences in episode duration; that is, rats performed longer face-grooming episodes in the small compared to the large observation cage. The present data confirm previous reports that isolated face grooming is a more sensitive measure than the total amount of face grooming. Bilateral IoN surgery does not seem to offer a more stable outcome measure; increases in isolated face grooming were, however, more clearly observed in the small cage.

Continuous administration of the 5-hydroxytryptamine1A agonist (3-Chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl) -amino]-methyl]piperidin-1-yl]-methadone (F 13640) attenuates allodynia-like behavior in a rat model of trigeminal neuropathic pain.

(3-Chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl]piperidin-1-yl]-methadone (F 13640) is a recently discovered high-efficacy 5-hydroxytryptamine (HT)1A receptor agonist that produces central analgesia through the neuroadaptive mechanisms of inverse tolerance and cooperation. In a rat model of trigeminal neuropathic pain, the chronic constriction injury of the infraorbital nerve causes allodynia-like behavior that develops within 2 weeks and remains stable thereafter. We report that early after surgery, during which time allodynia develops, the continuous 2-week infusion of 0.63 mg/day F 13640 inhibited the allodynia-like behavior, whereas 5 mg/day morphine showed no significant effect. When F 13640 infusion was initiated late after surgery, when allodynia was well established, it produced an antiallodynic effect that was apparent during the entire infusion period. In contrast, morphine infusion caused an initially marked antiallodynic effect to which tolerance developed within the 2-week infusion period. The GABA-B receptor agonist baclofen (1.06 mg/day) that has a recognized usefulness in the treatment of trigeminal neuralgia, demonstrated effectiveness in both conditions. The data are consistent with a theory of nociceptive signal transduction, as well as with previous data, in demonstrating the neuroadaptive mechanisms of inverse tolerance and cooperation. That is, in contrast with morphine, the antiallodynic effect induced by 5-HT1A receptor activation does not decay, but, if anything, grows with chronicity. Also, 5-HT1A receptor activation seemed to cooperate with nociceptive stimulation in, paradoxically, inducing an antiallodynic effect. The data presented here suggest that F 13640 may perhaps offer a lasting treatment of trigeminal neuralgia.

The 5-HT(1A) receptor agonist F 13640 attenuates mechanical allodynia in a rat model of trigeminal neuropathic pain.

The effects of acute intraperitoneal injections of the 5-HT(1A) receptor agonists F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl]piperidin-1-yl]-methadone] and F 13714 [3-chloro-4-fluorophenyl-(4-fluoro-4-[[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl]-piperidin-1-yl-methanone] were studied in comparison with those of baclofen and morphine on responsiveness to von Frey hair stimulation after chronic constriction injury to the rat's infraorbital nerve (IoN-CCI). Following IoN-CCI, an ipsilateral hyperresponsiveness developed that remained stable in control rats throughout the period of drug testing. F 13640, F 13714, baclofen and morphine dose-dependently decreased the hyperresponsiveness; normalization of the response occurred at doses 0.63, 0.04, 5 and 10 mg/kg, respectively. Confirming earlier data, baclofen's effects further validate IoN-CCI as a model of trigeminal neuralgia. The effects of F 13640 and F 13714 are initial evidence that 5-HT(1A) receptor agonists produce profound analgesia in the IoN-CCI model. The present data extend recent evidence that high-efficacy 5-HT(1A) receptor activation constitutes a new mechanism of central analgesia the spectrum of which may also encompass trigeminal neuropathic pain.

Comparison between two types of behavioral variables of non-evoked facial pain after chronic constriction injury to the rat infraorbital nerve.

BACKGROUND AND PURPOSE: Chronic constriction injury to the rat infraorbital nerve (IoN-CCI) was reported to induce asymmetric face grooming directed to the territory of the injured nerve, and localized mechanical allodynia. The model has been used for pharmacologic testing; responsiveness to mechanical stimulation has been used as outcome measure, but face grooming behavior was not studied in this context. METHODS: Face grooming data from a series of four experiments using the IoN-CCI model were retrospectively analyzed, and two types of face grooming were identified: on the one hand, isolated face grooming (i.e., face grooming that is neither preceded nor followed by body grooming); and on the other hand, face grooming during body grooming (i.e., face grooming that is part of more general body grooming behavior). RESULTS: In all four experiments, amount of isolated face grooming was found to be significantly increased after IoN-CCI. In contrast, the amount of face grooming during body grooming was not significantly altered after IoN-CCI in any of the four experiments. CONCLUSIONS: The amount of isolated face grooming is a more sensitive outcome measure of neuropathic pain than is the total amount of face grooming, which includes face grooming during body grooming.