Comparative study of the effects of ibuprofen, acetaminophen, and codeine in a model of orofacial postoperative pain in male and female rats.

Pain management is a primary goal after oral surgeries, but little is known about sex differences in the sensitivity to analgesics. This study aimed to compare the efficacy of three drugs with analgesic potential on heat and mechanical hyperalgesia, spontaneous pain and locomotion on male and female rats subjected to a model of orofacial postoperative pain. Male and female Wistar rats were submitted to intraoral incision or sham surgery, and on postoperative day 3, the effect of the ibuprofen (30 and 100 mg/kg), acetaminophen (100 and 300 mg/kg) and codeine (3 and 10 mg/kg) was assessed on responses to heat and mechanical facial stimulation, facial grooming, and locomotion. Ibuprofen reduced heat and mechanical hyperalgesia and grooming behavior in male and female rats in a non-sedative dose; acetaminophen dose-dependently reduced the mechanical hyperalgesia and abolished the heat hyperalgesia and the grooming behavior but caused sedation in both sexes; codeine dose-dependently reduced the mechanical hyperalgesia in male and female rats, and reduced the heat hyperalgesia, but females were less sensitive than males. It reduced spontaneous facial grooming in both sexes, but induced hyperlocomotion in females. Ibuprofen presented the most favorable profile, since it reduced over 50% heat and mechanical hyperalgesia in male and female rats, and significantly reduced spontaneous pain, without causing sedation or affecting locomotion. The identification of sex differences in the sensitivity and safety profile of frequently used analgesics can help guide the choice of more effective individualized therapies for pain control.

Sex differences in carbamazepine effects in a rat model of trigeminal neuropathic pain.

Carbamazepine (CBZ) represents the first-line treatment for trigeminal neuralgia, a condition of facial pain that affects mainly women. The chronic constriction of the infraorbital nerve (CCI-ION) is a widely used model to study this condition, but most studies do not include females. Thus, this study aimed to characterize sensory and affective changes in female rats after CCI-ION and compare the effect of CBZ in both sexes. Mechanical allodynia was assessed 15 days after CCI-ION surgery in rats treated with CBZ (10 and 30 mg/kg, i.p.) or vehicle, together with the open-field test. Independent groups were tested on the Conditioned Place Preference (CPP) paradigm and ultrasonic vocalization (USV) analysis. Blood samples were collected for dosage of the main CBZ metabolite. CBZ at 30 mg/kg impaired locomotion of CCI-ION male and sham and CCI-ION female rats and resulted in significantly higher plasma concentrations of 10-11-EPX-CBZ in the latter. Only male CCI-ION rats showed increased facial grooming which was significantly reduced by CBZ at 10 mg/kg. CBZ at 10 mg/kg significantly reduced mechanical allodynia and induced CPP only in female CCI-ION rats. Also, female CCI-ION showed reduced emission of appetitive USV but did not show anxiety-like behavior. In conclusion, male and female CCI-ION rats presented differences in the expression of the affective-motivational pain component and CBZ was more effective in females than males. Further studies using both sexes in trigeminal neuropathic pain models are warranted for a better understanding of potential differences in the pathophysiological mechanisms and efficacy of pharmacological treatments.

Antinociceptive and anxiolytic-like effects of Lavandula angustifolia essential oil on rat models of orofacial pain.

BACKGROUND: Nociceptive and inflammatory orofacial pain is highly prevalent in the population, which justifies the search for safer analgesics. There is increasing evidence of the analgesic and anxiolytic potential of Lavandula angustifolia essential oil (LAV EO), which may represent, when administered through inhalation, may represent a safer alternative for pain treatment. OBJECTIVE: to evaluate whether LAV EO has antinociceptive effect in the formalin test, and anti-hyperalgesic and anxiolytic-like effects in rats subjected to a model of orofacial postoperative pain. METHODOLOGY: Female Wistar rats were exposed to LAV EO (5%) by inhalation for 30 minutes. After exposure, animals were injected with formalin (2.5%, 50 µL) or saline into the hind paw or upper lip and the number of flinches or facial grooming time, respectively, were evaluated. Likewise, on day 3 after intraoral mucosa incision, the animals were exposed to LAV EO and facial mechanical, and heat hyperalgesia were assessed. The influence of LAV EO inhalation on anxiety-like behavior was assessed in operated rats by testing them on the open field (OF) and elevated plus maze (EPM). RESULTS: LAV EO reduced the phase II of the paw formalin test and both phases of the orofacial formalin test. On day three post-incision, LAV EO reduced heat and mechanical hyperalgesia, from 30 minutes up to three hours, and reduced the anxiety-like behavior in operated rats without causing locomotor deficit. CONCLUSION: LAV EO inhalation results in antinociceptive and anxiolytic-like effects in orofacial pain models, which encourages further studies on LAV EO indications and effectiveness on orofacial pain conditions.

Antinociceptive effect of ultra-low dose naltrexone in a pre-clinical model of postoperative orofacial pain.

Painmanagement after oral surgeries is essential to enhance recovery, reduce negative outcomes and improve the experience of the patient. Naltrexone (NTX) is a non-selective opioid receptor antagonist that has been shown to modulate neuro-inflammation when employed in low to ultra-low doses. In addition, ultra-low dose naltrexone (ULDN) has been shown to potentiate opioids' analgesia and to have opioid-sparing effects. Herein it was investigated the effect of ULDN in a model of postoperative orofacial pain in rats, and it was tested the hypothesis that blockade of TLR4-signalling pathway contributes to its antinociceptive effect. Systemic NTX reduced heat hyperalgesia in female rats and heat and mechanical hyperalgesia in male rats after incision surgery. Combined treatment with NTX and morphine, both at ineffective doses, resulted in a significant reduction of heat hyperalgesia in male rats. NTX injection at the incision site failed to change heat hyperalgesia, but injection at the trigeminal ganglion (TG) or subnucleus caudalis (Sp5C) caused a significant reduction in heat hyperalgesia. At these sites, blockade of TLR4 impeded NTX effect. Lipopolysaccharide (LPS) injection in the intraoral mucosa resulted in facial heat hyperalgesia an increase in IL-1ß levels in the TG, which were reduced by systemic NTX. Stimulation of macrophages with LPS resulted in increase of nitric oxide, IL-1ß and CXCL-2 levels which were reduced by NTX. Altogether, these results provide evidence for an antinociceptive effect of ULDN in postoperative orofacial pain and suggest that blockade of TLR4 and downstream signaling pathway contribute to its effect.

Cannabidiol enhances the antinociceptive effects of morphine and attenuates opioid-induced tolerance in the chronic constriction injury model.

Neuropathic pain (NP) is a complex health problem that includes sensorial manifestations such as evoked and ongoing pain. Cannabidiol (CBD) has shown potential in the treatment of NP and the combination between opioids and cannabinoids has provided promising results on pain relief. Thus, our study aimed to investigate the effect of treatment combination between CBD and morphine on evoked and ongoing pain, and the effect of CBD on morphine-induced tolerance in the model of chronic constriction injury (CCI) of the sciatic nerve in rats. Mechanical thresholds (i.e., evoked pain) were evaluated before and 7 days after surgery. We also employed a 4-day conditioned place preference (CPP) protocol, to evaluate relief of ongoing pain (6-9 days after surgery). Treatment with morphine (2 and 4 mg/kg) or CBD (30 mg/kg) induced a significant antinociceptive effect on evoked pain. The combination of CBD (30 mg/kg) and morphine (1 mg/kg) produced an enhanced antinociceptive effect, when compared to morphine alone (1 mg/Kg). Treatment with morphine (1 and 2 mg/kg) or CBD (30 mg/kg) alone failed to induce significant scores in the CPP test. However, combined treatment of CBD (30 mg/kg) and morphine (1 mg/kg) provided significant positive scores, increased the number of entrances in the drug-paired chamber in the CPP test and did not alter locomotor activity in rats. Lastly, treatment with CBD partially attenuated morphine-induced tolerance. In summary, our results support the indication of CBD as an adjuvant to opioid therapy for the attenuation of NP and opioid-induced analgesic tolerance.

Antinociceptive effects of bupivacaine and its sulfobutylether-ß-cyclodextrin inclusion complex in orofacial pain.

Bupivacaine hydrochloride (BVC) represents an option to produce long-lasting analgesia, and complexation in cyclodextrins has shown improvements in biopharmaceutical properties. This study aimed to characterize and test the cytotoxicity and antinociceptive effects of BVC complexed in sulfobutylether-ß-cyclodextrin (SBEßCD). The kinetics and stoichiometry of complexation and BVC-SBEßCD association constant were evaluated by phase solubility study and Job's plot. Evidence of the BVC-SBEßCD complex formation was obtained from scanning electron microscopy (SEM), infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). The cytotoxicity was evaluated in keratinocyte (HaCaT) and neuroblastoma (SH-SY5Y). Antinociceptive effects were registered via orofacial pain models: the formalin test, carrageenan-induced hyperalgesia, and postoperative pain (intraoral incision). The complex formation occurred at a 1:1 BVC-SBEßCD molar ratio, with a low association constant (13.2 M-1). SEM, DSC, and FTIR results demonstrated the host-guest interaction. The IC50% values determined in SH-SY5Y were 216 µM and 149 µM for BVC and BVC-SBEßCD, respectively (p < 0.05). There was no difference in HaCaT IC50%. In orofacial pain model, BVC-SBEßCD significantly prolonged antinociceptive effect, in about 2 h, compared to plain BVC. SBEßCD can be used as a drug delivery system for bupivacaine, whereas the complex showed long-lasting analgesic effects.

Trigeminal neuropathic pain reduces 50-kHz ultrasonic vocalizations in rats, which are restored by analgesic drugs.

Trigeminal neuralgia (TN) is a severe form of neuropathic pain frequently associated with anxiety. The chronic constriction injury of the infraorbital nerve (CCI-ION) of rodents is a well-established model to study sensory alterations related to TN. However, few studies have addressed the emotional component of pain, which is fundamental to increase its translational capability. Emission of ultrasonic vocalization (USV) is considered a reliable measure of the emotional state of rats. Rats emit 50-kHz USVs in social and appetitive situations, whereas 22-kHz USVs may index a negative state. Studies suggest that persistent pain causes reduction in 50-kHz calls, but this may also indicate anxiety-like behavior. Thus, we hypothesize that CCI-ION would decrease 50-kHz calls and that pharmacological pain relief would restore USVs, without interfering with anxiety-like behavior. On day 15 after surgery, male rats were treated with local lidocaine, midazolam or carbamazepine to determine their effect on facial mechanical hyperalgesia, USV and anxiety-like behavior. The results showed that CCI-ION induced hyperalgesia, which was attenuated by lidocaine or carbamazepine, developed anxiety-like behavior, which was reduced only by midazolam, and displayed a reduced number of 50-kHz calls, compared to sham. Lidocaine and carbamazepine increased 50-kHz calls emitted by CCI-ION rats, but midazolam failed to change them. These data add information on the translational aspects of CCI-ION model and carbamazepine treatment for trigeminal neuropathic pain. Furthermore, they suggest that the reduction of USV in persistent pain conditions is related to spontaneous pain and reinforce the idea that it reflects the emotional component of pain.

Blockade of kappa opioid receptors reduces mechanical hyperalgesia and anxiety-like behavior in a rat model of trigeminal neuropathic pain.

It has been shown that kappa opioid receptor (KOR) antagonists, such as nor-binaltorphimine (nor-BNI), have antinociceptive effects in some pain models that affect the trigeminal system. Also, its anxiolytic-like effect has been extensively demonstrated in the literature. The present study aimed to investigate the systemic, local, and central effect of nor-BNI on trigeminal neuropathic pain using the infraorbital nerve constriction model (CCI-ION), as well as to evaluate its effect on anxiety-like behavior associated with this model. Animals received nor-BNI systemically; in the trigeminal ganglion (TG); in the subarachnoid space to target the spinal trigeminal nucleus caudalis (Sp5C) or in the central amygdala (CeA) 14 days after CCI-ION surgery. Systemic administration of nor-BNI caused a significant reduction of facial mechanical hyperalgesia and promoted an anxiolytic-like effect, which was detected in the elevated plus-maze and the light-dark transition tests. When administered in the TG or CeA, the KOR antagonist was able to reduce facial mechanical hyperalgesia induced by CCI-ION, but without changing the anxiety-like behavior. Moreover, no change was observed on nociception and anxiety-like behavior after nor-BNI injection into the Sp5C. The present study demonstrated antinociceptive and anxiolytic-like effects of nor-BNI in a model of trigeminal neuropathic pain. The antinociceptive effect seems to be dissociated from the anxiolytic-like effect, at both the sites involved and at the dose need to achieve the effect. In conclusion, the kappa opioid system may represent a promising target to be explored for the control of trigeminal pain and associated anxiety. However, further studies are necessary to better elucidate its functioning and modulatory role in chronic trigeminal pain states.

Antinociceptive and anxiolytic-like effects of Lavandula angustifolia essential oil on rat models of orofacial pain

Abstract Nociceptive and inflammatory orofacial pain is highly prevalent in the population, which justifies the search for safer analgesics. There is increasing evidence of the analgesic and anxiolytic potential of Lavandula angustifolia essential oil (LAV EO), which may represent, when administered through inhalation, may represent a safer alternative for pain treatment. Objective to evaluate whether LAV EO has antinociceptive effect in the formalin test, and anti-hyperalgesic and anxiolytic-like effects in rats subjected to a model of orofacial postoperative pain. Methodology Female Wistar rats were exposed to LAV EO (5%) by inhalation for 30 minutes. After exposure, animals were injected with formalin (2.5%, 50 μL) or saline into the hind paw or upper lip and the number of flinches or facial grooming time, respectively, were evaluated. Likewise, on day 3 after intraoral mucosa incision, the animals were exposed to LAV EO and facial mechanical, and heat hyperalgesia were assessed. The influence of LAV EO inhalation on anxiety-like behavior was assessed in operated rats by testing them on the open field (OF) and elevated plus maze (EPM). Results LAV EO reduced the phase II of the paw formalin test and both phases of the orofacial formalin test. On day three post-incision, LAV EO reduced heat and mechanical hyperalgesia, from 30 minutes up to three hours, and reduced the anxiety-like behavior in operated rats without causing locomotor deficit. Conclusion LAV EO inhalation results in antinociceptive and anxiolytic-like effects in orofacial pain models, which encourages further studies on LAV EO indications and effectiveness on orofacial pain conditions.

Acute orofacial pain leads to prolonged changes in behavioral and affective pain components.

Acute pain that persists for a few days is associated with a reduction in patients' quality of life. Orofacial persistent pain promotes psychological disorders such as anxiety, impairs daily essential activities such as eating, and results in decreased social interaction. Here, we investigated whether rats subjected to orofacial formalin injection or intraoral incision surgery display persistent facial heat hyperalgesia, ongoing pain, anxiety-like behavior, and changes in ultrasonic vocalization. Orofacial formalin injection or intraoral incision caused facial heat hyperalgesia for 3 days compared with saline-injected and sham animals. In addition, both experimental groups showed a reduction in the number of entries and in the time spent in the open arms in the elevated plus maze test on day 3, suggesting that anxiety-like behavior developed as a consequence of persistent pain. At this time point, both groups also displayed a reduction in the number of 50-kHz calls, specifically in the flat subtype, which suggests a decrease in social communication. Moreover, on day 3 after surgery, systemic morphine produced robust conditioned place preference in rats subjected to intraoral incision compared with sham, and the former group also presented increased spontaneous facial grooming, revealing the presence of ongoing pain. Finally, Western blot and immunohistochemistry analysis showed a reduction in tyrosine hydroxylase expression in the nucleus accumbens, which may reflect a decrease in mesolimbic dopaminergic activity. Altogether, the results demonstrate that acute orofacial pain causes prolonged changes in behavioral and affective pain components, which may be related to dopaminergic changes in the nucleus accumbens.

The opposing contribution of neurotrophin-3 and nerve growth factor to orofacial heat hyperalgesia in rats.

It has been proposed that neurotrophin-3 acts in a manner that is opposed to nerve growth factor, especially in the modulation of heat hyperalgesia. Injury to the constriction of the infraorbital nerve (CION) is a well-established model of trigeminal neuropathic pain that leads to robust heat, cold, and mechanical hyperalgesia. Here, we assessed the effect of local neurotrophin-3 treatment on CION-induced hyperalgesia, and we examined some mechanisms related to the effect of neurotrophin-3. Neurotrophin-3 (1 µg/50 µl) injected into the upper lip of CION rats caused a significant and long-lasting reduction of CION-induced heat hyperalgesia, but failed to affect cold and mechanical hyperalgesia. Increased levels of neurotrophin-3 were detected in the injured nerve at the time point that represents the peak of heat hyperalgesia. The anti-hyperalgesic effect of neurotrophin-3 was markedly reduced in the presence of an antagonist of TrkA receptors (K-252a, 1 µg/50 µl). Moreover, association of lower doses of neurotrophin-3 with an antibody anti-nerve growth factor resulted in a synergistic anti-hyperalgesic effect in CION rats. Local injection of nerve growth factor (3 µg/50 µl) or the TRPV1 agonist capsaicin (1 µg/50 µl), but not neurotrophin-3 injection (1 µg/50 µl), resulted in long-lasting facial heat hyperalgesia, which was both significantly reduced by previous neurotrophin-3 local treatment. In conclusion, we suggest that neurotrophin-3 is a potent modulator of facial heat hyperalgesia, which may exert an inhibitory influence on the trkA pathway. Neurotrophin-3 treatment may represent a promising approach, especially in pain conditions associated with increased levels of nerve growth factor.

Blockade of peripheral endothelin receptors abolishes heat hyperalgesia and spontaneous nociceptive behavior in a rat model of facial cancer.

OBJECTIVE: To improve understanding of the pathophysiology of cancer-induced facial nociception, by evaluating the contribution of peripheral endothelin receptors in tumor-induced facial heat hyperalgesia, increased spontaneous grooming, as well as ongoing nociception in a rat model of facial cancer. DESIGN: The study was conducted using 396 rats. Facial cancer was induced by inoculating a suspension of Walker-256 cells into the rats' right vibrissal pad. Facial heat hyperalgesia and spontaneous grooming were assessed on day 6, while the conditioned place preference (CPP) test was performed on days 3-6 after tumor cells inoculation. Rats received local injections of the non-peptidic dual ETA/ETB endothelin receptors antagonist, bosentan (10 and 30 µg/50 µL), single or combined injections of peptidic ETA and ETB endothelin receptors antagonists (BQ-123 and BQ-788, at 20 ug/50 µL, each), or of lidocaine (1 mg/50 µl) and morphine (30 µg/50 µL). RESULTS: Bosentan, lidocaine and morphine local treatment all attenuated tumor-induced heat hyperalgesia (p < 0.05) and spontaneous facial grooming (p < 0.05). However, BQ-123 and BQ-788 did not modify tumor-induced heat hyperalgesia or the spontaneous facial grooming (p > 0.05). Whether this difference in effectiveness is due to receptor affinity or to pharmacokinetic factors still needs to be explored. Local injection of bosentan, lidocaine or morphine failed to control ongoing nociception, as evidenced by the absence of CPP in tumor-bearing rats (p > 0.05). CONCLUSION: Endothelins, acting through peripheral ETA and ETB receptors, may play a significant role on the development of heat hyperalgesia and increased spontaneous grooming associated to facial cancer in rats.

Blockade of endothelin receptors reduces tumor-induced ongoing pain and evoked hypersensitivity in a rat model of facial carcinoma induced pain.

Pain reported by patients with head and neck cancer is characterized as persistent pain with mechanical allodynia. Pain management is inadequate for many patients, highlighting the need for improved therapies. We examined the hypothesis that the mixed endothelin ETA and ETB receptor antagonist, bosentan, reduces tumor-induced ongoing pain and evoked hypersensitivity in a rat model of facial cancer pain. Facial cancer was induced by inoculating a suspension of Walker-256 cells into the rat's right vibrissal pad. Tumor-bearing rats developed heat and tactile hypersensitivity along with increased spontaneous grooming behavior. Systemic morphine (2.5mg/kg, s.c.) blocked tumor-induced thermal and tactile hypersensitivity, with a lower dose (0.625mg/kg, s.c.) effective only against thermal hypersensitivity. Systemic bosentan blocked tumor-induced thermal hypersensitivity only at a high (300mg/kg, p.o.) dose, but failed to modify tactile hypersensitivity. Co-administration of the low doses of bosentan and morphine resulted in improved reduction of the tumor-induced heat and tactile hypersensitivity compared to either dose alone. Bosentan (100mg/kg, p.o.) reduced spontaneous grooming and induced conditioned place preference (CPP) selectively in tumor-bearing rats, suggesting that bosentan reduces tumor-induced ongoing pain at a lower dose than required to block tumor-induced hypersensitivity. This study provides evidence that endothelins may mediate tumor-induced ongoing pain and thermal hypersensitivity. In addition, bosentan enhanced morphine's effects on blocking tumor-induced heat and tactile hypersensitivity indicating that endothelin antagonists may be beneficial therapeutic targets that can be used to manage cancer-induced facial pain with opioid-sparing effects.

Facial pain and anxiety-like behavior are reduced by pregabalin in a model of facial carcinoma in rats.

Pain and anxiety are common symptoms in head and neck cancer patients. The anticonvulsant pregabalin has therapeutic indication for the treatment of pain and anxiety, and may represent a useful drug for both conditions. Thus, the aim of this study was to investigate the relationship between pain and anxiety in rats with facial carcinoma, as the influence of pregabalin treatment in both aspects. Facial carcinoma was induced by subcutaneous inoculation of Walker-256 tumor cells in the vibrissa pad of Wistar rats. On day 6 after inoculation spontaneous facial grooming and conditioned place preference were assessed as non-evoked pain measurements and facial mechanical hyperalgesia were assessed 3 and 6 days after tumor cells inoculation. Moreover, anxiety-like behavior was evaluated on the elevated plus maze and light-dark transition tests at the same time points. The effect of pregabalin treatment (30 mg/kg, p.o.) was evaluated in all tests. Our results demonstrated that pregabalin treatment reduced the spontaneous facial grooming and induced conditioned place preference 6 days post tumor inoculation. Tumor-bearing rats developed mechanical hyperalgesia starting 3 days post tumor induction, which was also significant on day 6, but the anxiety-like behavior was detected only in tumor-bearing rats that developed mechanical hyperalgesia and only six days after tumor cells inoculation. Both, the mechanical hyperalgesia and the anxiety-like behavior related to the tumor were significantly reduced by pregabalin treatment on day 6. Pregabalin treatment resulted in antinociceptive and anxiolytic-like effects on facial tumor-bearing rats and may represent a promising therapeutic option for cancer patients.

Evaluation of heat hyperalgesia and anxiety like-behaviors in a rat model of orofacial cancer.

Pain and anxiety are commonly experienced by cancer patients and both significantly impair their quality of life. Some authors claim that there is a relationship between pain and anxiety, while others suggest that there is not a direct association. In any case, there is indeed a consensus that anxiety impairs the pain condition beyond be under diagnosed and undertreated in cancer pain patients. Herein we investigated if rats presenting heat hyperalgesia induced by orofacial cancer cell inoculation would display anxiety-like behaviors. In addition, we evaluated if pain blockade would result in alleviation of anxiety behaviors, as well as, if blockade of anxiety would result in pain relief. Orofacial cancer was induced in male Wistar rats by inoculation of Walker-256 cells into the right vibrissal pad. Heat facial hyperalgesia was assessed on day 6 after the inoculation, and on this time point rats were submitted to the elevated plus maze and the light-dark transition tests. The influence of lidocaine and midazolam on heat hyperalgesia and anxiety-like behaviors was assessed. The peak of facial heat hyperalgesia was detected 6 days after cancer cells inoculation, and at this time point, rats exhibited increased anxiety-like behaviors. Local treatment with lidocaine (2%/50µL) caused a marked reduction of heat hyperalgesia, but failed to affect the anxiety-like behaviors, while midazolam (0.5mg/kg, i.p.) treatment failed to change the heat threshold, but induced an anxiolytic-like effect. Altogether, our data demonstrated that rats with orofacial cancer present pain- and anxiety-like behaviors, but brief heat hyperalgesia relief does not affect the anxiety-like behaviors, and vice-versa, in our experimental conditions.

Pregabalin reduces acute inflammatory and persistent pain associated with nerve injury and cancer in rat models of orofacial pain.

AIMS: To assess the analgesic effect of pregabalin in orofacial models of acute inflammatory pain and of persistent pain associated with nerve injury and cancer, and so determine its effectiveness in controlling orofacial pains having different underlying mechanisms. METHODS: Orofacial capsaicin and formalin tests were employed in male Wistar rats to assess the influence of pregabalin (or vehicle) pretreatment in acute pain models, and the results from these experiments were analyzed by one-way analysis of variance (ANOVA) followed by Newman Keuls post-hoc test. Pregabalin (or vehicle) treatment was also tested on the facial heat hyperalgesia that was evaluated in rats receiving injection of the inflammatory irritant carrageenan into the upper lip, as well as after constriction of the infraorbital nerve (a model of trigeminal neuropathic pain), or after inoculation of tumor cells into the facial vibrissal pad; two-way repeated measures ANOVA followed by Newman-Keuls post-hoc test was used to analyze data from these experiments. RESULTS: Facial grooming induced by capsaicin was abolished by pretreatment with pregabalin at 10 and 30 mg/kg. However, pregabalin failed to modify the first phase of the formalin response, but reduced the second phase at both doses (10 and 30 mg/kg). In addition, treatment of rats with pregabalin reduced the heat hyperalgesia induced by carrageenan, as well as by nerve injury and facial cancer. CONCLUSION: Pregabalin produced a marked antinociceptive effect in rat models of facial inflammatory pain as well as in facial neuropathic and cancer pain models, suggesting that it may represent an important agent for the clinical control of orofacial pain.

Clinical aspects and pharmacological treatment of trigeminal neuralgia

Introduction: Trigeminal neuralgia (TN) is defined as sudden, usually unilateral, severe and brief pain episodes within the distribution of one or more branches of the trigeminal nerve. In some patients a constant background pain may persist, additionally to pain attacks, which can make difficult to differentiate the trigeminal neuralgia from other orofacial pain types. Objective: To review the classification, physiopathological aspects, epidemiologic data and pharmacological options to control pain related to trigeminal neuralgia. Literature review: One of the proposed etiologies for this condition is a localcircumscribed demyelination of the trigeminal nerve resulting in neuronal hyperexcitability and generation of ephaptic coupling, which would be responsible for the pain paroxysms. Initially, the treatment of patients with these pain characteristics is based on the use of anticonvulsants, in order to attenuate the ectopic-generated pain impulses. Carbamazepine is the first-line drug, but other anticonvulsants may be employed and have shown variable efficacy in the treatment of trigeminal neuralgia. Conclusion: According to the new classification of the International Headache Society, classic trigeminal neuralgia is divided in purely paroxysmal and with concomitant persistent facial pain. The pathophysiology is unclear, but trigeminal neuralgia seems to be the consequence of vascular compression of the trigeminal nerve near the brain stem. Although TN presents a low prevalence in general population (i.e. 5-30 new patients per 100,000), trigeminal neuralgia is an important clinical concern both by pain severity and difficulty of its satisfactory control. Anticonvulsants are the medication of choice in the treatment of trigeminal neuralgia; however, their use is associated with several adverse effects and possibility of treatment refractoriness.

Kinin B(1) and B(2) receptors contribute to orofacial heat hyperalgesia induced by infraorbital nerve constriction injury in mice and rats.

Mechanisms coupled to kinin B(1) and B(2) receptors have been implicated in sensory changes associated to various models of neuropathy. The current study aimed to investigate if kinins also participate in orofacial thermal hyperalgesia induced by constriction of the infraorbital nerve (CION), a model of trigeminal neuropathic pain which displays persistent hypersensitivity to orofacial sensory stimulation, in rats and mice. Male Swiss mice (30-35g) or Wistar rats (200-250g; n=6-10 per group in both cases) underwent CION or sham surgery and were submitted repeatedly to application of heat ( approximately 50 degrees C) to the ipsilateral or contralateral snout, delivered by a heat source placed 1cm from the vibrissal pad. Decreases in latency to display head withdrawal or vigorous snout flicking were considered indicative of heat hyperalgesia. CION caused long-lasting heat hyperalgesia which started on Day 2 after surgery in both species and lasted up to Day 17 in mice and Day 10 in rats. Administration of DALBK or HOE-140 (peptidic B(1) and B(2) receptor antagonists, respectively; each at 3nmol in 10microl) onto the exposed infraorbital nerve of mice at the moment of surgery delayed the development of the thermal hyperalgesia. Systemic treatment on Day 5 (mice) or Day 4 (rats) with Des-Arg(9), Leu(8)-Bradykinin (DALBK, B(1) receptor antagonist, 0.1-1micromol/kg, i.p.) or HOE-140 (B(2) receptor antagonist, 0.001-1micromol/kg, i.p.) transiently reduced heat hyperalgesia in both species. Due to the peptidic nature of DALBK and HOE-140, it is likely that their effects reported herein resulted from blockade of peripheral kinin receptors. Thus, mechanisms operated by kinin B(1) and B(2) receptors, contribute to orofacial heat hyperalgesia induced by CION in both mice and rats. Perhaps kinin B(1) and B(2) receptor antagonists might constitute effective preventive and curative treatments for orofacial thermal hyperalgesia induced by nerve injury.

Endothelin ET(B) receptor antagonist reduces mechanical allodynia in rats with trigeminal neuropathic pain.

Trigeminal neuropathic pain, which is associated with marked orofacial mechanical allodynia, is frequently refractory to currently available drugs. Because endothelins (ETs) can contribute to nociceptive changes in animal models of inflammatory, cancer, and diabetic neuropathic pain, the present study evaluated the influence of ET(A) and ET(B) receptor antagonists on orofacial mechanical allodynia in a rat model of trigeminal neuropathic pain. Unilateral constriction (C) of the infraorbital nerve (ION) caused pronounced and sustained bilateral mechanical allodynia, evaluated by application of von Frey hairs to the vibrissal pad. Mechanical allodynia on postoperative days 12-15 after nerve injury was abolished for up to 90 mins by subcutaneous administration of 2.5 mg/kg morphine, but was fully refractory to intravenous (iv) administration of 10 mg/kg of the dual ET(A) plus ET(B) or selective ET(A) receptor antagonists, bosentan and atrasentan, respectively. In sharp contrast, iv administration of 20 mg/kg of the selective ET(B) receptor antagonist, A-192621, caused a net 61 +/- 15% reduction of mechanical threshold, lasting 2 hrs. Co-injection of atrasentan plus A-192621 did not modify ION injury-induced mechanical allodynia. Injection of 10 pmol ET-1 into the upper lip of naive rats caused ipsilateral mechanical allodynia lasting up to 5 hrs. Thus, ET(B) receptor-mediated mechanisms contribute to orofacial mechanical allodynia induced by CION injury, but, some-how, functional ET(A) receptors are required for expression of the antiallodynic effect of ET(B) receptor blockade.