Infraorbital Nerve Constriction Research Articles

B vitamins relieve neuropathic pain behaviors induced by infraorbital nerve constriction in rats

AimsThere is mounting evidence that use of B vitamins can help control neuropathic pain. This study investigated if treatment with B1, B6 and B12 vitamins, alone or in combination with carbamazepine, can ameliorate distinct nociceptive behaviors in a model of trigeminal neuropathic pain. Main methodsMale Wistar rats were submitted to infraorbital nerve constriction or sham surgery and received a 5-day treatment with one of the B vitamins, a single carbamazepine injection or the association of both treatments and were tested for facial thermal and mechanical hyperalgesia at different time intervals. Key findingsRepeated treatment with B1 (thiamine), B6 (pyridoxine) and B12 (cyanocobalamin) vitamins (at 180, 180 and 18mg/kg/day, respectively, for 5days) prevented the development of heat hyperalgesia after infraorbital nerve injury, but only B12 and B6 treatments attenuated cold and mechanical hyperalgesia, respectively. A single injection of carbamazepine (30mg/kg) significantly reduced thermal, but not mechanical, hyperalgesia after nerve injury. Combinations of lower doses of each B vitamin (B1 and B6 at 18mg/kg/day and B12 at 1.8mg/kg/day for 5days) with carbamazepine (10mg/kg) markedly reduced heat hyperalgesia after infraorbital nerve injury. Treatment with B12 (1.8mg/kg/day) combined with carbamazepine (10mg/kg) also synergized to attenuate cold hyperalgesia at some time points, but combination of B6 (18mg/kg/day) with carbamazepine (30mg/kg) failed to modify mechanical hyperalgesia. SignificanceWe suggest that B vitamins might constitute a relevant adjuvant to control some aspects of the pain afflicting patients suffering from trigeminal neuropathic pain.

Cyclotraxin-B, a New TrkB Antagonist, and Glial Blockade by Propentofylline, Equally Prevent and Reverse Cold Allodynia Induced by BDNF or Partial Infraorbital Nerve Constriction in Mice

Several lines of evidence indicate that brain-derived neurotrophic factor (BDNF) plays a key role as a central pronociceptive modulator of pain, acting through postsynaptic TrkB receptors that trigger intracellular signaling cascades leading to central sensitization. The overall aim of this study was to investigate to what extent BDNF could participate in the generation and maintenance of trigeminal neuropathic pain. The results showed that acute intracisternal administration of nanogram doses of BDNF in naïve mice elicited long-lasting, dose-related, cold allodynic responses to topical application of acetone onto vibrissal pad skin. The systemic administration of cyclotraxin-B (CTX-B), a new TrkB receptor antagonist, or propentofylline, an inhibitor of glial activation, was able to either prevent or reverse the effects of intracisternal BDNF on cold nociception. In addition, the blockade of TrkB receptor by CTX-B inhibited the mechanisms that either initiate or maintain cold allodynia in the ipsilateral vibrissal pad skin after unilateral constriction of the infraorbital nerve. These observations raise the possibility that BDNF is capable on its own of conveying many features of the signaling mechanisms that underlie central sensitization caused by nerve constriction. PerspectiveAlthough further studies are necessary to examine in detail the mechanisms underlying the strong anti-allodynic action of CTX-B, this compound may represent an interesting lead for the development of novel therapeutic strategies aimed at preventing and/or suppressing central sensitization associated with neuropathic pain.

Central Action of Peripherally Applied Botulinum Toxin Type A on Pain and Dural Protein Extravasation in Rat Model of Trigeminal Neuropathy

BackgroundInfraorbital nerve constriction (IoNC) is an experimental model of trigeminal neuropathy. We investigated if IoNC is accompanied by dural extravasation and if botulinum toxin type A (BoNT/A) can reduce pain and dural extravasation in this model.Methodology/Principal FindingsRats which developed mechanical allodynia 14 days after the IoNC were injected with BoNT/A (3.5 U/kg) into vibrissal pad. Allodynia was tested by von Frey filaments and dural extravasation was measured as colorimetric absorbance of Evans blue - plasma protein complexes. Presence of dural extravasation was also examined in orofacial formalin-induced pain. Unilateral IoNC, as well as formalin injection, produced bilateral dural extravasation. Single unilateral BoNT/A injection bilaterally reduced IoNC induced dural extravasation, as well as allodynia (lasting more than 2 weeks). Similarly, BoNT/A reduced formalin-induced pain and dural extravasation. Effects of BoNT/A on pain and dural extravasation in IoNC model were dependent on axonal transport through sensory neurons, as evidenced by colchicine injections (5 mM, 2 µl) into the trigeminal ganglion completely preventing BoNT/A effects.Conclusions/SignificanceTwo different types of pain, IoNC and formalin, are accompanied by dural extravasation. The lasting effect of a unilateral injection of BoNT/A in experimental animals suggests that BoNT/A might have a long-term beneficial effect in craniofacial pain associated with dural neurogenic inflammation. Bilateral effects of BoNT/A and dependence on retrograde axonal transport suggest a central site of its action.

Intradermal injection of Botulinum toxin type A alleviates infraorbital nerve constriction‐induced thermal hyperalgesia in an operant assay

Recent studies have shown that infraorbital nerve constriction (IoNC)-induced mechanical allodynia has been attenuated by administration of highly purified 150-kDa Botulinum neurotoxin type A (BoNT/A). Here, we extend these studies to determine whether BoNT/A could attenuate IoNC-induced symptoms of thermal hyperalgesia. Instead of testing head withdrawal thresholds, a thermal operant assay was used to evaluate cortical processing of sensory input following IoNC. In this assay, a fasted rat's desire to obtain a food reward (sweetened condensed milk) is coupled to its ability to tolerate facial contact with a warm (45 °C) thermode. Bilateral IoNC decreased the ratio of thermode contact duration/event, which is an indicative of thermal hyperalgesia. BoNT/A injection intradermally in the area of infraorbital nerve (IoN) innervation 7 days after IoNC resulted in decreased number of facial contacts and increased the ratio of contact duration/event (measured at 14 days after IoNC). The BoNT/A (2-200 pg) effects were dose dependent and statistically significant at 100 and 200 pg (P < 0·05). Complete reversal of thermal hyperalgesia symptoms was obtained with a 200-pg dose, without affecting sham rat behaviour. Off-site (neck) injection of BoNT/A did not relieve thermal hyperalgesia, while co-injection of BoNT/A with a neutralising antibody in the area of IoN innervation prevented relief of thermal hyperalgesia. Neither IoNC nor BoNT/A injection affected operant assay parameters with a 24 °C thermode, indicating selectivity of thermal hyperalgesia measurements. These results strongly suggest that intradermal injection of BoNT/A in the area of IoN innervation alleviates IoNC-induced thermal hyperalgesia in an operant assay.

Kinin B1 and B2 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.

Botulinum toxin type a (150 kDa) decreases exaggerated neurotransmitter release from trigeminal ganglion neurons and relieves neuropathy behaviors induced by infraorbital nerve constriction

Many patients with trigeminal neuropathies suffer severe chronic pain which is inadequately alleviated with centrally-acting drugs. These drugs also possess severe side effects making compliance difficult. One strategy is to develop new treatments without central side effects by targeting peripheral sensory neurons, since sensory neuron excitability and neurotransmitter release increase in chronic pain states. Such treatments may include the highly purified botulinum toxin type A 150 kDa (BoNT/A) which reportedly blocks vesicular neurotransmitter release. We set out to determine if experimental trigeminal neuropathy induced by infraorbital nerve constriction (IoNC) in rats could alter neurotransmitter release from somata of trigeminal sensory neurons and if it could be attenuated by BoNT/A. Thus, we monitored the secretory activity of acutely dissociated trigeminal ganglion (TRG) neurons from naïve and IoNC rats by measuring the fluorescence intensity of the membrane-uptake marker (N-(3-triethylammoniumpropyl)-4-(6-(4-(diethylamino)phenyl)hexatrienyl)pyridinium dibromide (FM4-64). FM4-64 staining showed that neurons possess a pool of recycled vesicles which could be released by high KCl (75 mM) application. BoNT/A pre-treatment of acutely dissociated TRG neurons from naïve rats significantly reduced the rate of FM4-64 dye release. Neurons isolated from TRG ipsilateral to IoNC exhibited significantly faster onset of FM4-64 release than neurons contralateral to IoNC (sham surgery). IoNC also produced long-lasting ipsilateral tactile allodynia, measured as large decreases of withdrawal thresholds to mechanical stimulation. Intradermal injection of BoNT/A in the area of infraorbital branch of the trigeminal nerve (IoN) innervation alleviated IoNC-induced mechanical allodynia and reduced the exaggerated FM4-64 release in TRG neurons from these rats. Our results suggest that BoNT/A decreases neuropathic pain behaviors by decreasing the exaggerated neurotransmitter release from TRG sensory neurons.

Mechanisms operated by endothelin ETA and ETB receptors in the trigeminal ganglion contribute to orofacial thermal hyperalgesia induced by infraorbital nerve constriction in rats

Endothelins, acting through specific endothelin ET(A) and/or ET(B) receptors, participate in nociceptive processing in models of cancer, inflammatory and neuropathic pain. The present study investigated which cell types express endothelin receptors in the trigeminal ganglion, and the contribution of mechanisms mediated by endothelin ET(A) and ET(B) receptors to orofacial heat hyperalgesia induced by unilateral constriction of the infraorbital nerve (CION). Both receptor types were identified by immunohistochemistry in the trigeminal ganglion, ET(A) receptors on small-sized non-myelinated and myelinated A-fibers and ET(B) receptors on both satellite glial cells and small-sized non-myelinated neuronal cells. CION promoted ipsilateral orofacial heat hyperalgesia which lasted from Day 2 until Day 10 after surgery. Ongoing CION-induced heat hyperalgesia (on Day 4) was reduced transiently, but significantly, by systemic or local treatment with antagonists of endothelin ET(A) receptors (atrasentan, 10 mg/kg, i.v.; or BQ-123, 10 nmol/lip), endothelin ET(B) receptors (A-192621, 20 mg/kg, i.v.; or BQ-788, 10 nmol/ lip), or of both ET(A)/ET(B) receptors (bosentan, 10 mg/kg, i.v.; or BQ-123 plus BQ-788, each at 10 nmol/lip). On the other hand, CION-induced heat hyperalgesia was transiently abolished over the first 90 min following i.p. injection of morphine hydrochloride (2.5 mg/kg), but fully resistant to reversal by indomethacin (4 mg/kg, i.p.) or celecoxib (10 mg/kg, i.p.). Thus, heat hyperalgesia induced by CION is maintained, in part, by peripheral signaling mechanisms operated by ET(A) and ET(B) receptors. Endothelin receptors might represent promising therapeutic targets for the control of trigeminal neuropathic pain.

The effect of peripheral administration of botulinum toxin type A in rats with neuropathic pain

There are many trigeminal neuropathic pain (TN) patients in the world and they are suffering severe chronic pain. These patients are taking central acting drugs with severe side effects that make it difficult for the patients to continue the drugs. Our final goal is to develop new treatment methods that decrease chronic pain without severe side effects. To decrease the central side effects, our target is peripheral sensory ganglia. Experimental animal models of TN and sciatic neuralgia have been developed. We investigated the changes of mechanical allodynia after injecting newly developed botulinum toxin type A (150 kDa) (BoNT) peripherally to rats with sciatic nerve entrapment (SNE) or infraorbital nerve constriction (INC). SNE was induced by placing three Tygon® cuffs around the sciatic nerve, and INC was induced by ligating loosely around the infraorbital nerve. After SNE or INC induction, significant decreases of withdrawal thresholds to mechanical stimulation (Model 1601C, IITC Instruments) were observed in the hindpaw or face. Peripheral intradermal injection of BoNT, which is reported to block vesicular neurotransmitter release, recovered the withdrawal thresholds. These results suggest that SNE or INC rat models show neuropathic pain signs and BoNT decreases the neuropathic pain by decreasing the neurotransmitter release. Supported by Science and Culture in Japan 18390512 and Ryobi Teien Memorial Foundation.

Orofacial cold hyperalgesia due to infraorbital nerve constriction injury in rats: Reversal by endothelin receptor antagonists but not non-steroidal anti-inflammatory drugs

The susceptibility of changes in responsiveness to noxious cold stimulation of rats submitted to chronic constriction of the infraorbital nerve (CION) or carrageenan to drug inhibition was compared. Nocifensive responses were measured as total time rats engaged in bilateral facial grooming with both forepaws over the first 2 min following tetrafluoroethane spray application to the snout. Carrageenan (50 μg, s.c. into upper lip) caused short-lived ipsilateral cold hyperalgesia (peak at 3 h: vehicle 8.4 ± 1.3, carrageenan 21.2 ± 3.0 s) which was markedly suppressed by i.p. indomethacin (4 mg/kg), celecoxib (10 mg/kg) or s.c. dexamethasone (0.5 mg/kg), endothelin ET A or ET B receptor antagonists (BQ-123 and BQ-788, respectively; 10 nmol/lip). CION caused ipsilateral cold hyperalgesia between Days 2 and 12, which peaked on Days 4 (sham 15.3 ± 1.8, CION 32.4 ± 5.3 s) to 6. Established peak CION-induced cold hyperalgesia was unaffected by indomethacin and celecoxib, whereas dexamethasone, BQ-123, BQ-788, and i.v. injections of selective antagonists of ET A (atrasentan, 3–10 mg/kg) or ET B (A-192621, 5–20 mg/kg) receptors caused significant inhibitions lasting 1–2.5 h (peaks ∼65–90%). Bosentan (dual ET A/ET B receptor antagonist, 10 mg/kg, i.v.) abolished CION-induced cold hyperalgesia for up to 6 h. Thus, once established, CION-induced orofacial hyperalgesia to cold stimuli appears to lack an inflammatory component, but is alleviated by endothelin ET A and/or ET B receptor antagonists. If this CION injury model bears predictive value to trigeminal neuralgia (i.e., paroxysmal orofacial pain triggered by various stimuli), endothelin receptors might constitute new targets for treatment of this disorder.

Effect of MK‐801, memantine and lamotrigine on cold and heat hypernociception in trigeminal neuropathic pain

This study evaluated the effects of the anticonvulsant lamotrigine (LAM) and NMDA receptor antagonists memantine (MEM) and MK-801 in the trigeminal hypernociception triggered by heat or cold after infraorbital nerve (ION) constriction. Trigeminal neuropathy was induced in male Wistar rats by two ligatures around the ION. Sham animals were submitted to the same procedure without ION ligatures. At 4 and 6 days after surgery (maximal hypernociception for cold and heat, respectively), sham and constricted groups received LAM (30 mg/Kg, ip), MEM (0.3–3 mg/Kg, po) or MK-801 (5 nM/50 μL, in the lip) or vehicle and noxious cold (tetrafluorethane spray) or heat (radiant heat) stimulus was applied at 30 min intervals for 6h, ipsilaterally to the surgery. Facial grooming time and latency for flicking snout/vibrissae was recorded as an index of nociceptive responsiveness. ION injury increased the total facial grooming time for cold stimulation from 8.6 ± 1.3 to 28.9 ± 2.9 s and reduced the reaction time after heat stimulation from 10.6 ± 0.4 to 4.2 ± 0.4 s. LAM, MEN and MK-801 reduced the cold hypernociception by 95%, 97% and 51% and the heat hypernociception by 87%, 92% and 49%, respectively. The results suggest that LAM, MEM and MK-801 are effective in the reversal of the cold and heat hypernociception after ION contriction and that local glutamate release may have a role in the maintenance of this condition. Sup. CAPES/Fund. Araucária.

Inflammatory hypersensitivity in a rat model of trigeminal neuropathic pain

Thermal and mechanical stimuli have been used to monitor the development of neuropathic pain following an experimental injury to a branch of the trigeminal nerve. However, the response to inflammatory challenge has not been evaluated in a model of orofacial neuropathic pain. The purpose of this study was to determine whether chronic constriction of the infraorbital nerve (IoN) enhances nociceptive responses elicited by the formalin test. The characteristic biphasic response (primarily directed grooming) to formalin injected subcutaneously in the right vibrissae pad was observed in sham-injury rats. Twenty-one days after IoN constriction, formalin injection provoked an immediate response that involved both directed grooming and other abnormal behaviors, e.g. flinching, trismus and shielding of the affected region. As with sham-injury rats, this was followed by a quiescent period and then a second phase of nocifensive behaviors. The total time recorded for all pain-related behaviors was significantly greater in rats with constrictive injuries ( P<0.001), due primarily to the exhibition of novel pain-related responses. Histological examination (qualitative) revealed that chronic constriction resulted in a ligature-induced neuroma, as well as a partial denervation of the affected sensory field. Thus, an intense inflammatory hypersensitivity in a rat model of orofacial neuropathic pain develops in association with partial denervation and with an ongoing perineural inflammatory response and neuroma formation.

TEMPOL, a radical scavenger, reduces thermal hyperalgesia and NADPH‐d expression in the neurons of trigeminal ganglion of rats with infraorbital nerve constriction

AbstractNo medical or surgial treatments have been reported to permanently stop trigeminal pain attacks. TEMPOL, a stable nitroxide radical scavenger, has been recently shown efficient in providing neuroprotection. Here we tested the efficiency of TEMPOL in alleviating heat hyperalgesia and expression of NADPH‐d in trigeminal afferent neurons of rats with experimentally induced secondary trigeminal neuralgia by chronic constriction of infraorbitary nerve. The results showed that TEMPOL significantly reduced heat hyperalgesia and induced a large decrease of NADPH‐d in neurons of the Gasser ganglia. These findings suggest that the radical scavengers like TEMPOL could be new therapeutic strategies to treat neuropathic pain induced by infraorbital nerve constriction.

TEMPOL, a radical scavenger, reduces thermal hyperalgesia and NADPH-d expression in the neurons of trigeminal ganglion of rats with infraorbital nerve constriction

No medical or surgial treatments have been reported to permanently stop trigeminal pain attacks. TEMPOL, a stable nitroxide radical scavenger, has been recently shown efficient in providing neuroprotection. Here we tested the efficiency of TEMPOL in alleviating heat hyperalgesia and expression of NADPH-d in trigeminal afferent neurons of rats with experimentally induced secondary trigeminal neuralgia by chronic constriction of infraorbitary nerve. The results showed that TEMPOL significantly reduced heat hyperalgesia and induced a large decrease of NADPH-d in neurons of the Gasser ganglia. These findings suggest that the radical scavengers like TEMPOL could be new therapeutic strategies to treat neuropathic pain induced by infraorbital nerve constriction.

Interleukin-6 and nerve growth factor levels in peripheral nerve and brainstem after trigeminal nerve injury in the rat

Earlier studies have demonstrated that inflammation plays a role in the development of evoked pain following partial nerve injury. In this report, we demonstrate bilateral changes in interleukin-6 (IL-6) and nerve growth factor (nerve growth factor) levels following unilateral infraorbital nerve (infraorbital nerve) constriction. infraorbital nerve constriction resulted in an initial period of decreased mechanical sensitivity (1 and 3 days), followed by recovery (7 days) and then a marked bilateral mechanical hypersensitivity (10 and 28 days). nerve growth factor levels in the injured infraorbital nerve were elevated on all days, but peak concentrations of nerve growth factor were observed on day 3. A smaller increase was also observed on days 1, 3, and 7 in the uninjured nerve. A bilateral elevation of IL-6 was also seen on days 3 and 10 in the infraorbital nerve, and in the brainstem on days 3, 7 and 10 after constriction. No changes in mechanical sensitivity were found after a sham-injury, but there was a small increase in brainstem IL-6 ipsilaterally at 7 days. We conclude from these data that increases in IL-6 and nerve growth factor may contribute to the development of mechanical allodynia after trigeminal nerve injury, but they are not specifically correlated with the onset or duration of pain behaviors.