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1.
Prog Neuropsychopharmacol Biol Psychiatry ; 38(2): 149-58, 2012 Aug 07.
Article in English | MEDLINE | ID: mdl-22449477

ABSTRACT

We demonstrate the establishment of a novel animal model for trigeminal neuropathic pain following compression of the trigeminal nerve root, which produces prolonged nociceptive behavior and demyelination of the trigeminal nerve root. Under anesthesia, male Sprague-Dawley rats (200-230 g) were mounted onto a stereotaxic frame and injections of a 4% agar solution (10 µl) were given to achieve compression of the trigeminal nerve root. A sham operation was performed using identical procedures but without agar injections. Nociceptive behavior was examined 3 days before and then at 3, 7, 10, 14, 17, 21, 24, 30, 40, 55, and 70 days after the surgery. Compression of the trigeminal nerve root caused mechanical allodynia, hyperalgesia, and cold hypersensitivity. Mechanical allodynia was established within 3 days and recovered to preoperative levels on postoperative day (POD) 40. Mechanical hyperalgesia and cold hypersensitivity persisted until 55 days following compression. The compression produced focal demyelination in the trigeminal nerve root. In the medullary dorsal horn, phospho-p38 (p-p38) mitogen-activated protein kinase (MAPK) was found to be exclusively expressed in the microglia on POD 14. Furthermore, intraperitoneal administration of carbamazepine (50mg/kg) significantly blocked mechanical allodynia and reduced p38 MAPK activation induced by the compression of the trigeminal nerve root. Our findings suggest that prolonged nociceptive behavior following compression of the trigeminal nerve root may mimic trigeminal neuralgia in this animal model and that the activation of p38 MAPK in the microglia contributes to pain hypersensitivity in rats that have undergone compression of the trigeminal nerve root.


Subject(s)
Facial Pain/physiopathology , Hyperalgesia/physiopathology , Neuralgia/physiopathology , Nociception/physiology , Trigeminal Nerve/physiopathology , Animals , Behavior, Animal/physiology , Disease Models, Animal , Male , Pain Measurement , Rats , Rats, Sprague-Dawley , Trigeminal Ganglion/physiology
2.
Article in English | MEDLINE | ID: mdl-22019843

ABSTRACT

The present study investigated the role of microglia and p38 MAPK in the development of mechanical allodynia in rats with compression of the trigeminal ganglion. Male Sprague-Dawley rats weighing 250-260 g were used. Under pentobarbital sodium anesthesia, the animals were mounted onto a stereotaxic frame and given injections of 4% agar solution (10 µL) to compress the trigeminal ganglion. The air-puff thresholds significantly decreased after compression of the trigeminal ganglion. On postoperative day 14, immunoreactivity to both OX-42 and p-p38 MAPK was up-regulated in the medullary dorsal horn as compared to the sham group. P-p38 MAPK was found to be co-localized with OX-42, but not with NeuN, a neuronal cell marker, or with GFAP, an astroglial cell marker. Intracisternal administration of 100 µg of minocycline significantly inhibited both mechanical allodynia and activation of microglia produced by compression of the trigeminal ganglion. Intracisternal administration of 0.1, 1, or 10 µg of SB203580, a p38 MAPK inhibitor, also significantly decreased mechanical allodynia and p38 MAPK activation in the trigeminal ganglion-compressed group. These results suggest that activation of p38 MAPK in the microglia is an important step in the development of mechanical allodynia in rats with compression of the trigeminal ganglion and that the targeted blockade of microglial p38 MAPK pathway is a potentially important new treatment strategy for trigeminal neuralgia-like nociception.


Subject(s)
Hyperalgesia/drug therapy , Microglia , Nerve Compression Syndromes , Trigeminal Ganglion , Animals , Hyperalgesia/enzymology , Imidazoles/pharmacology , Male , Microglia/drug effects , Microglia/enzymology , Microglia/metabolism , Nerve Compression Syndromes/drug therapy , Nerve Compression Syndromes/enzymology , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Trigeminal Ganglion/drug effects , Trigeminal Ganglion/enzymology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/biosynthesis
3.
Mol Pain ; 7: 57, 2011 Aug 05.
Article in English | MEDLINE | ID: mdl-21816109

ABSTRACT

BACKGROUND: We investigated the differential regulation of p-p38 MAPK or p-NF-κB in male Sprague-Dawley rats with inferior alveolar nerve injury resulting from mal-positioned dental implants. For this purpose, we characterized the temporal expression of p-p38 MAPK or p-NF-κB in the medullary dorsal horn and examined changes in nociceptive behavior after a blockade of p-p38 MAPK or p-NF-κB pathways in rats with trigeminal neuropathic pain. RESULTS: Under anesthesia, the left lower second molar was extracted and replaced with a mini dental implant to intentionally injure the inferior alveolar nerve. Western and immunofluorescence analysis revealed that p-p38 MAPK is upregulated in microglia following nerve injury and that this expression peaked on postoperative day (POD) 3 through 7. However, the activation of p-NF-κB in astrocyte peaked on POD 7 through 21. The intracisternal administration of SB203580 (1 or 10 µg), a p38 MAPK inhibitor, on POD 3 but not on POD 21 markedly inhibits mechanical allodynia and the p-p38 MAPK expression. However, the intracisternal administration of SN50 (0.2 or 2 ng), an NF-κB inhibitor, on POD 21 but not on POD 3 attenuates mechanical allodynia and p-NF-κB expression. Dexamethasone (25 mg/kg) decreases not only the activation of p38 MAPK but also that of NF-κB on POD 7. CONCLUSIONS: These results suggest that early expression of p-p38 MAPK in the microglia and late induction of p-NF-κB in astrocyte play an important role in trigeminal neuropathic pain and that a blockade of p-p38 MAPK at an early stage and p-NF-κB at a late stage might be a potential therapeutic strategy for treatment of trigeminal neuropathic pain.


Subject(s)
Behavior, Animal , NF-kappa B/metabolism , Neuralgia/enzymology , Neuralgia/pathology , Trigeminal Nerve/enzymology , Trigeminal Nerve/pathology , p38 Mitogen-Activated Protein Kinases/metabolism , Analgesics/pharmacology , Animals , Behavior, Animal/drug effects , Dexamethasone/pharmacology , Fluorescent Antibody Technique , Imidazoles/pharmacology , Male , NF-kappa B/antagonists & inhibitors , Peptides/pharmacology , Phosphorylation/drug effects , Protein Transport/drug effects , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Time Factors , Trigeminal Nerve/drug effects , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
4.
Mol Pain ; 7: 46, 2011 Jun 08.
Article in English | MEDLINE | ID: mdl-21651766

ABSTRACT

BACKGROUND: We investigated the role of the central NMDA receptor NR2 subunits in the modulation of nociceptive behavior and p-p38 MAPK expression in a rat model with compression of the trigeminal nerve root. To address this possibility, changes in air-puff thresholds and pin-prick scores were determined following an intracisternal administration of NR2 subunit antagonists. We also examined effects of NR2 subunit antagonists on the p-p38 MAPK expression. RESULTS: Experiments were carried out using male Sprague-Dawley rats weighing (200-230 g). Compression of the trigeminal nerve root was performed under pentobarbital sodium (40 mg/kg) anesthesia. Compression of the trigeminal nerve root produced distinct nociceptive behavior such as mechanical allodynia and hyperalgesia. Intracisternal administration of 10 or 20 µg of D-AP5 significantly increased the air-puff threshold and decreased the pin-prick scores in a dose-dependent manner. The intracisternal administration of PPPA (1, 10 µg), or PPDA (5, 10 µg) increased the air-puff threshold and decreased the pin-prick scores ipsilateral as well as contralateral to the compression of the trigeminal root. Compression of the trigeminal nerve root upregulated the expression of p-p38 MAPK in the ipsilateral medullary dorsal horn which was diminished by D-AP5, PPPA, PPDA, but not Ro25-6981. CONCLUSIONS: Our findings suggest that central NMDA receptor NR2 subunits play an important role in the central processing of trigeminal neuralgia-like nociception in rats with compression of the trigeminal nerve root. Our data further indicate that the targeted blockade of NR2 subunits is a potentially important new treatments strategy for trigeminal neuralgia-like nociception.


Subject(s)
Behavior, Animal , Nociceptors/metabolism , Radiculopathy/enzymology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Spinal Nerve Roots/pathology , Trigeminal Nerve/pathology , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Behavior, Animal/drug effects , Diazonium Compounds/administration & dosage , Diazonium Compounds/pharmacology , Drug Administration Routes , Male , Motor Activity/drug effects , Nociceptors/drug effects , Nociceptors/pathology , Phenols/administration & dosage , Phenols/pharmacology , Phosphorylation/drug effects , Piperidines/administration & dosage , Piperidines/pharmacology , Pyridines/administration & dosage , Pyridines/pharmacology , Radiculopathy/pathology , Radiculopathy/physiopathology , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/metabolism , Spinal Nerve Roots/drug effects , Spinal Nerve Roots/enzymology , Spinal Nerve Roots/physiopathology , Trigeminal Nerve/drug effects , Trigeminal Nerve/enzymology , Trigeminal Nerve/physiopathology , Up-Regulation/drug effects
5.
Pain ; 146(1-2): 114-20, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19665300

ABSTRACT

We have previously reported a novel method for producing chronic nociceptive behavior in rats following compression of the trigeminal ganglion. In the present study, we have further studied the role of demyelination in the development of prolonged nociceptive behavior in the trigeminal territory. For this purpose, lysophosphatidic acid (LPA) was injected into the trigeminal ganglia of male Sprague-Dawley rats weighing between 250 and 260 g. Under pentobarbital sodium anesthesia, the rats were mounted onto a stereotaxic frame and 3 microL of LPA (1 nmol) solution was injected into the trigeminal ganglion to produce demyelination. This treatment decreased the air-puff thresholds both ipsilateral and contralateral to the injection site, which persisted until postoperative day 100 and returned to the preoperative levels 130 days after the LPA injection. The LPA injection also produced a significant ipsilateral hyper-responsiveness to pin-prick stimulation. The effects of DGPP, an LPA1/3 receptor antagonist, and Y-27632, a Rho kinase inhibitor, upon LPA-induced mechanical allodynia and hyperalgesia were also investigated. Pretreatment with DGPP blocked both mechanical allodynia and ipsilateral hyperalgesia. However, pretreatment with Y-27632 blocked only ipsilateral and contralateral mechanical allodynia. These results thus indicate that a targeted blockade of LPA receptor and Rho kinase pathways are potentially important new treatments for demyelination-induced trigeminal neuralgia-like nociception.


Subject(s)
Behavior, Animal/physiology , Demyelinating Diseases/chemically induced , Lysophospholipids/pharmacology , Pain/chemically induced , Pain/psychology , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/psychology , Trigeminal Ganglion/physiology , Animals , Demyelinating Diseases/pathology , Enzyme Inhibitors/pharmacology , Functional Laterality/drug effects , Hot Temperature , Hyperalgesia/chemically induced , Hyperalgesia/psychology , Injections , Lysophospholipids/administration & dosage , Male , Physical Stimulation , Rats , Rats, Sprague-Dawley , Reaction Time/drug effects , Receptors, Lysophosphatidic Acid/antagonists & inhibitors , Receptors, Lysophosphatidic Acid/genetics , rho-Associated Kinases/antagonists & inhibitors
6.
Eur J Pain ; 13(6): 568-75, 2009 Jul.
Article in English | MEDLINE | ID: mdl-18774318

ABSTRACT

The present study is the first demonstration of prolonged nociceptive behavior in the trigeminal region following compression of the trigeminal ganglion in rats. Experiments were carried out on male Sprague-Dawley rats mounted onto a stereotaxic frame under pentobarbital sodium anesthesia. For compression of the trigeminal ganglion, a 4% agar solution (8microl) was injected into the trigeminal ganglion through a stainless steel injector (24 gauge), which extended 2mm beyond the end of a guide cannula (21 gauge). Following agar injection, the injector and guide cannula were removed. In the control group, rats were sham operated without agar injection. Air-puff thresholds (mechanical allodynia), pin prick responses (mechanical hyperalgesia), and spontaneous scratching behavior were examined 3 days before surgery and at 3, 7, 10, 14, 17, 21, 24, 30, and 40 days after surgery. Data were analyzed using a repeated measures ANOVA followed by multiple group comparisons using the LSD post-hoc test. Air-puff thresholds significantly decreased after compression of the trigeminal ganglion. Mechanical allodynia was established within 3 days and lasted beyond postoperative day 24. Mechanical hyperalgesia was also evident 3 days after compression and persisted until the 40th postoperative day. Although mechanical allodynia and hyperalgesia appeared bilaterally, the ipsilateral side was significantly more sensitive. Intraperitoneal treatment with carbamazepine significantly blocked mechanical allodynia produced by compression of the trigeminal ganglion. These findings suggest that prolonged nociceptive behavior following compression of the trigeminal ganglion may mimic trigeminal neuralgia in this animal model.


Subject(s)
Pain/psychology , Trigeminal Ganglion/physiology , Trigeminal Neuralgia/psychology , Agar , Analgesics, Non-Narcotic/pharmacology , Animals , Behavior, Animal/physiology , Body Weight/physiology , Carbamazepine/pharmacology , Facial Pain/psychology , Functional Laterality/drug effects , Grooming/drug effects , Hyperalgesia/drug therapy , Hyperalgesia/psychology , Male , Pain/etiology , Pain/pathology , Pain Measurement/drug effects , Physical Stimulation , Postural Balance/drug effects , Pressure , Rats , Rats, Sprague-Dawley , Trigeminal Ganglion/pathology , Trigeminal Neuralgia/pathology
7.
Eur J Pain ; 12(3): 361-70, 2008 Apr.
Article in English | MEDLINE | ID: mdl-17768078

ABSTRACT

The present study investigated the role of peripheral opioid receptors in mustard oil-induced nociceptive behavior and inflammation in the masseter muscles of lightly anesthetized rats. Experiments were carried out on male Sprague-Dawley rats weighing between 300 and 400 g. After initial anesthesia with sodium pentobarbital (40 mg/kg, i.p.), one femoral vein was cannulated and connected to an infusion pump for the intravenous infusion of sodium pentobarbital. The rate of infusion was adjusted to provide a constant level of anesthesia. Mustard oil (MO, 30 microl) was injected into the mid-region of the left masseter muscle via a 30-gauge needle. Intramuscularly-administered morphine significantly reduced shaking behavior but not MO-induced inflammation. Intramuscular pretreatment with naloxone, an opioid receptor antagonist, reversed antinociception produced by intramuscularly-administered morphine, while intracisternal administration of naloxone did not affect the antinociception of peripheral morphine. Pretreatment with d-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), a mu opioid receptor antagonist, but not naltrindole, a delta opioid receptor antagonist, nor norbinaltorphimine (nor-BNI), a kappa opioid receptor antagonist, reversed intramuscularly-administered morphine-induced antinociception. These results indicate that intramuscularly-administered morphine produces antinociception in craniofacial muscle nociception and that this intramuscularly-administered morphine-induced antinociception is mediated by a peripheral mu opioid receptor. Our observations further support the clinical approach of administering opioids in the periphery for the treatment of craniofacial muscle nociception.


Subject(s)
Analgesics/therapeutic use , Masseter Muscle/physiopathology , Morphine/therapeutic use , Mustard Plant/toxicity , Narcotic Antagonists/pharmacology , Pain/prevention & control , Plant Oils/toxicity , Analgesics/administration & dosage , Analgesics/pharmacology , Anesthesia, General , Animals , Inflammation/chemically induced , Injections , Injections, Intramuscular , Male , Masseter Muscle/drug effects , Morphine/administration & dosage , Morphine/pharmacology , Naloxone/pharmacology , Naltrexone/analogs & derivatives , Naltrexone/pharmacology , Nociceptors/drug effects , Nociceptors/physiology , Pain/chemically induced , Pain/physiopathology , Plant Oils/administration & dosage , Psychomotor Performance/drug effects , Rats , Rats, Sprague-Dawley , Receptors, Opioid, delta/antagonists & inhibitors , Receptors, Opioid, kappa/antagonists & inhibitors , Receptors, Opioid, mu/antagonists & inhibitors , Single-Blind Method , Somatostatin/analogs & derivatives , Somatostatin/pharmacology
8.
Prog Neuropsychopharmacol Biol Psychiatry ; 31(6): 1322-9, 2007 Aug 15.
Article in English | MEDLINE | ID: mdl-17618720

ABSTRACT

The present study investigated the role of mitogen-activated protein kinase (MAPK) in orofacial neuropathic pain following chronic constriction injury of the infraorbital nerve (ION-CCI). Experiments were carried out on male Sprague-Dawley rats weighing between 200 and 230 g. The ION was separated from adhering tissue, and two ligatures (5-0 chromic gut) were tied loosely around it. We examined the air-puff thresholds (mechanical allodynia), scores of pinprick (mechanical hyperalgesia), and face grooming frequency for acetone application (hypersensitivity for cold stimulation) - 3, 3, 6, 9, 12, 15, 20, 25, 30, and 40 days after surgery. ION-CCI produced mechanical allodynia, hyperalgesia, and cold hypersensitivity. We investigated whether administration of MAPKs inhibitors blocks ION-CCI-induced mechanical allodynia. Intracisternal administration with PD98059 or SB203580, a MEK inhibitor or a p38 MAPK inhibitor, respectively, significantly inhibited ION-CCI-induced mechanical allodynia in the orofacial area. These results indicate that the ION-CCI produced behavioral alterations in the orofacial area and those central MAPKs pathways contribute to orofacial neuropathic pain. Our findings suggest that MAPKs inhibitors have a potential role in treatment for orofacial neuropathic pain.


Subject(s)
Enzyme Inhibitors/administration & dosage , Facial Pain/drug therapy , Flavonoids/administration & dosage , Hyperalgesia/drug therapy , Imidazoles/administration & dosage , Pyridines/administration & dosage , Animals , Behavior, Animal , Body Weight , Constriction , Disease Models, Animal , Dose-Response Relationship, Drug , Facial Pain/complications , Functional Laterality , Hyperalgesia/etiology , Male , Physical Stimulation , Rats , Rats, Sprague-Dawley , Sensory Thresholds/drug effects , Time Factors
9.
Neurosci Lett ; 409(3): 173-8, 2006 Dec 06.
Article in English | MEDLINE | ID: mdl-17030435

ABSTRACT

The present study investigated the role of peripheral groups I and II metabotropic glutamate receptors (mGluRs) in interleukin (IL)-1beta-induced mechanical allodynia in the orofacial area of rats. Subcutaneous injection of 10 pg of IL-1beta decreased air-puff thresholds ipsilateral or contralateral to the injection site. The decrease in air-puff thresholds appeared 10 min after the injection of IL-1beta and IL-1beta-induced mechanical allodynia persisted for over 3 h. Pre-treatment with 7-(hydroxyimino) cyclopropa[b] chromen-1a-carboxylate ethyl ester (CPCCOEt) or 2-methyl-6-(phenylethynyl)-pyridine hydrochloride (MPEP), a mGluR1 or mGluR5 antagonist, blocked IL-1beta-induced mechanical allodynia and mirror-image mechanical allodynia produced by a subcutaneous injection of 10 pg of IL-1beta. However, post-treatment with CPCCOEt or MPEP did not affect changes in behavioral responses, which were produced by the IL-1beta injection. Pre-treatment, as well as post-treatment with (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC), a group II mGluR agonist, blocked either IL-1beta-induced mechanical allodynia or mirror-image mechanical allodynia. The anti-allodynic effects of APDC were abolished by pre-treatment with (2S)-2-amino-2[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), a group II mGluR antagonist. These results indicate that peripheral group II mGluRs are involved in the development and maintenance of IL-1beta-induced mechanical allodynia, while peripheral group I mGluRs are involved in the development of IL-1beta-induced mechanical allodynia. Based on our observations, the peripheral application of group II mGluR agonists may be of therapeutic value in treating inflammatory pain.


Subject(s)
Facial Pain/metabolism , Hyperesthesia/metabolism , Interleukin-1beta , Receptors, Metabotropic Glutamate/metabolism , Touch/drug effects , Animals , Consciousness , Facial Pain/chemically induced , Hyperesthesia/chemically induced , Rats
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