mdl-100907 and Neuralgia

Chronic pain and sleep have a bidirectional relationship that promotes a vicious circle making chronic pain more difficult to treat. Therefore, pain and sleep should be treated simultaneously. In our previous study, we suggested that hyperactivation of ascending serotonergic neurons could cause secondary sleep disturbance in chronic pain. This study aimed to demonstrate the effects of a tricyclic antidepressant (amitriptyline) and a selective 5-hydroxy-tryptamine 2A (5-HT2A) antagonist (MDL 100907) that adjust serotonergic transmission, on secondary sleep disturbance induced in a preclinical chronic pain model. We produced a chronic neuropathic pain model by partial sciatic nerve ligation in mice, analyzed their electroencephalogram (EEG) and electromyogram (EMG) using the SleepSign software, and evaluated the sleep condition of the pain model mice after administration of amitriptyline or MDL 100907. Amitriptyline improved thermal hyperalgesia and the amount of sleep, especially non-REM sleep. Time change of normalized power density of δ wave in the nerve ligation group with amitriptyline administration showed a normal pattern that was similar to sham mice. In addition, MDL 100907 normalized sleep condition similar to amitriptyline, without improvement in pain threshold. In conclusion, amitriptyline could improve sleep quantity and quality impaired by chronic pain. 5-HT2A receptor antagonism could partially contribute to this sleep improvement, but is not associated with pain relief.

Topics: Amitriptyline; Animals; Antidepressive Agents, Tricyclic; Chronic Pain; Disease Models, Animal; Fluorobenzenes; Male; Mice; Neuralgia; Piperidines; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Sleep Wake Disorders

The amygdala plays a key role in emotional-affective aspects of pain and in pain modulation. The central nucleus (CeA) serves major amygdala output functions related to emotional-affective behaviors and pain modulation. Our previous studies implicated the corticotropin-releasing factor (CRF) system in amygdala plasticity and pain behaviors in an arthritis model. We also showed that serotonin (5-HT) receptor subtype 5-HT

Topics: Amygdala; Animals; Disease Models, Animal; Gene Knockdown Techniques; Male; Neuralgia; Neurons; Rats; Receptor, Serotonin, 5-HT2C; Receptors, Corticotropin-Releasing Hormone; Serotonin 5-HT2 Receptor Antagonists

Citral (3,7-dimethyl-2,6-octadienal) is an open-chain monoterpenoid present in the essential oils of several medicinal plants. The aim of this work was to evaluate the effects of orally administered citral in experimental models of acute and chronic nociception, inflammation, and gastric ulcers caused by non-steroidal anti-inflammatory drugs (NSAIDs). Oral treatment with citral significantly inhibited the neurogenic and inflammatory pain responses induced by intra-plantar injection of formalin. Citral also had prophylactic and therapeutic anti-nociceptive effects against mechanical hyperalgesia in plantar incision surgery, chronic regional pain syndrome, and partial ligation of sciatic nerve models, without producing any significant motor dysfunction. In addition, citral markedly attenuated the pain response induced by intra-plantar injection of glutamate and phorbol 12-myristate 13-acetate (PMA, a protein kinase C activator), as well as by intrathecal (i.t.) injection of ionotropic and metabotropic glutamate receptor agonists (N-methyl-D-aspartic acid [NMDA] and 1-amino-1,3-dicarboxycyclopentane [trans-ACPD], respectively), substance P, and cytokine tumour necrosis factor-α. However, citral potentiated behaviours indicative of pain caused by i.t., but not intra-plantar, injection of a transient receptor potential vanilloid receptor type 1 (TRPV1) agonist. Finally, the anti-nociceptive action of citral was found to involve significant activation of the 5-HT2A serotonin receptor. The effect of citral was accompanied by a gastro-protective effect against NSAID-induced ulcers. Together, these results show the potential of citral as a new drug for the treatment of pain.

Topics: Acute Pain; Acyclic Monoterpenes; Analgesics; Animals; Capsaicin; Chronic Pain; Excitatory Amino Acids; Formaldehyde; Glutamic Acid; Hyperalgesia; Ischemia; Ketanserin; Male; Mice; Monoterpenes; Neuralgia; Pain, Postoperative; Rats, Wistar; Receptor, Serotonin, 5-HT2A; Serotonin 5-HT2 Receptor Antagonists; Stomach Ulcer; Substance P; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha

Our previous study has demonstrated that topical and systemic administration of the 5-HT(2A) receptor antagonist ketanserin attenuates neuropathic pain. To explore the mechanisms involved, we examined whether ketanserin reversed the plasticity changes associated with calcitonin gene-related peptides (CGRP) and neuropeptide Y (NPY) which may reflect distinct mechanisms: involvement and compensatory protection. Behavioral responses to thermal and tactile stimuli after spinal nerve ligation (SNL) at L5 demonstrated neuropathic pain and its attenuation in the vehicle- and ketanserin-treated groups, respectively. SNL surgery induced an increase in CGRP and NPY immunoreactivity (IR) in laminae I-II of the spinal cord. L5 SNL produced an expression of NPY-IR in large, medium and small diameter neurons in dorsal root ganglion (DRG) only at L5, but not adjacent L4 and L6. Daily injection of ketanserin (0.3 mg/kg, s.c.) for two weeks suppressed the increase in CGRP-IR and NPY-IR in the spinal cord or DRG. The present study demonstrated that: (1) the expression of CGRP was enhanced in the spinal dorsal horn and NPY was expressed in the DRG containing injured neurons, but not in the adjacent DRG containing intact neurons, following L5 SNL; (2) the maladaptive changes in CGRP and NPY expression in the spinal cord and DRG mediated the bioactivity of 5-HT/5-HT(2A) receptors in neuropathic pain and (3) the blockade of 5-HT(2A) receptors by ketanserin reversed the evoked upregulation of both CGRP and NPY in the spinal cord and DRG contributing to the inhibition of neuropathic pain.

Topics: Animals; Calcitonin Gene-Related Peptide; Denervation; Disease Models, Animal; Ganglia, Spinal; Hyperalgesia; Immunohistochemistry; Ketanserin; Male; Neuralgia; Neuronal Plasticity; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Serotonin 5-HT2 Receptor Antagonists; Spinal Cord; Spinal Nerves; Up-Regulation

We investigated the effect of 5-HT receptor antagonists on mechanical hyperalgesia observed in a neuropathic pain rat model prepared by chronic constriction injury of the sciatic nerve. NAN-190, a 5-HT 1A receptor antagonist, (-)-pindolol, a 5-HT 1A/1B receptor antagonist, and tropisetron, a 5-HT(3/4) receptor antagonist, did not affect the pain threshold in the hyperalgesic hind limb to the same extent as in the normal hind limb. However, sarpogrelate and ketanserin, 5-HT 2A receptor antagonists, significantly elevated the pain threshold in the hyperalgesic hind limb, but not in the normal hind limb. In spite of its high affinity for the 5-HT 2A receptor, methysergide only slightly elevated the pain threshold in the hyperalgesic hind limb. Pre-treatment with methysergide significantly antagonized the inhibitory effect of sarpogrelate on hyperalgesia. Furthermore, the 5-HT 2A receptor specific binding activity of 3H-ketanserin determined for the hyperalgesic hind limb did not differ from that of the normal hind limb. From these results, we propose that the 5-HT 2A receptor in the hyperalgesic hind paw function as an agonist-independent active receptor following constriction of the sciatic nerve, and that sarpogrelate and ketanserin act as inverse agonists of this receptor and suppress its activation. Methysergide may act as a neutral antagonist that blocks the effect of inverse agonists on the 5-HT 2A receptor.

Topics: Animals; Binding Sites; Binding, Competitive; Denervation; Disease Models, Animal; Drug Interactions; Hyperalgesia; Ketanserin; Ligation; Male; Neuralgia; Pain Threshold; Peripheral Nerves; Peripheral Nervous System Diseases; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Sciatic Neuropathy; Sensory Receptor Cells; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Succinates

Intrathecal administration of serotonin type 2 (5-HT(2)) receptor agonists, alpha-methyl-5-hydroxytryptamine maleate (alpha-m-5-HT) or (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DOI), produces antiallodynic effects in a rat model of neuropathic pain. In the present study, we examined the antiallodynic effects of intrathecally administered agents which are selective for 5-HT(2C) receptors. Allodynia was produced by tight ligation of the left L5 and L6 spinal nerves, and was measured by applying von Frey filaments to the left hindpaw. Administration of the 5-HT(2C) receptor agonist, 6-chloro-2-(1-piperazinyl)-pyrazine (MK212; 3-100 microg), 1-(m-chlorophenyl)-piperazine (mCPP; 30-300 microg), or 1-(m-trifluoromethylphenyl)-piperazine (TFMPP; 30-300 microg), produced antiallodynic effects in a dose-dependent manner with no associated motor weakness. The ED(50) values of MK212, mCPP, and TFMPP were 39.2, 119.9, and 191.9 microg, respectively. Intrathecal pretreatment with the selective 5-HT(2C) receptor antagonist RS-102221 (30 microg) diminished the effects of the highest doses of 5-HT(2C) receptor agonists. The preferential 5-HT(2A) receptor antagonist ketanserin (30 microg) did not reverse the effects. In contrast to 5-HT(2C) receptor agonists, the antiallodynic effects of intrathecally administered alpha-m-5-HT (30 microg) and DOI (100 microg) were reversed by ketanserin, but not by RS-102221. These results indicate that 5-HT(2C) receptors have a role in spinal inhibition of neuropathic pain, and the effects produced by intrathecal administration of 5-HT(2C) receptor agonists are mediated by a mechanism different from that of alpha-m-5-HT or DOI, which seem to produce their effects through 5-HT(2A) receptors.

Topics: Amphetamines; Animals; Indoles; Injections, Spinal; Ketanserin; Ligation; Lumbar Vertebrae; Male; Neuralgia; Nociceptors; Piperazines; Pyrazines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2C; Serotonin; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Serotonin Receptor Agonists; Spinal Nerves; Spiro Compounds; Sulfonamides; Thiophenes