dizocilpine-maleate and Toothache

We have identified tooth pulp-driven neurons (TPDNs) in the thalamic mediodorsal nucleus (MD) in rats and showed that the TPDNs' responsiveness in the MD is increased by chemical conditioning stimulation of allyl-isothiocyanate (mustard oil) to the molar tooth pulp. The aim of the present study was to address the role of N-methyl-d-aspartate receptors (NMDA receptors) in the sensitized central nervous system following the mustard oil application to the rat tooth pulp. Microinjection of MK-801, a noncompetitive NMDA receptor antagonist, to the thalamic MD nucleus reduced the TPDNs' responsiveness in the thalamic MD nucleus. Gene expression analysis showed that expression levels of NMDA receptor subunits NR2A and NR2D mRNAs in the thalamus were increased by the mustard oil application and that the increases were reduced by MK-801. When naloxone, an opioid receptor antagonist, was given systemically following the MK801 microinjection, the TPDNs' responsiveness was rekindled and expression levels of NR2D and NR2A mRNAs were increased. Moreover, lidocaine pretreatment abolished the mustard oil-induced upregulation of NR2D and NR2A mRNAs. These results suggest that, during central sensitization, interaction of NMDA receptors and endogeneous opioid-related inhibitory mechanisms plays critical role in the alteration of the TPDNs' responsiveness in the thalamic MD nucleus.

Topics: Afferent Pathways; Anesthetics, Local; Animals; Dental Pulp; Dizocilpine Maleate; Dorsomedial Hypothalamic Nucleus; Efferent Pathways; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Hyperalgesia; Irritants; Lidocaine; Male; Molar; Mustard Plant; Naloxone; Narcotic Antagonists; Neuronal Plasticity; Plant Oils; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Sensory Receptor Cells; Toothache

The aim of the present study was to determine whether there is a convergence of inputs from tooth pulp (TP) and the superior sagittal sinus (SSS) on rat C1 spinal neurons, and to examine the effects of iontophoretically applied N-methyl-D: -aspartate (NMDA) and non-NMDA receptor antagonists on the SSS-evoked activity of C1 neurons. Extracellular single unit-recordings were made from 20 C1 units responding to TP electrical stimulation with a constant temporal relationship to a digastric electromyogram signal, using a multibarrel electrode in pentobarbital-anesthetized rats. Ninety percent of C1 neurons (18/20) responding to TP stimulation also responded to the SSS stimulation. These neurons were considered to be SSS-afferent inputs from Adelta-fibers (5.8 +/- 0.6 m/s; n = 18), based on the calculation of nerve conduction velocity. After the iontophoretic application (30, 50, and 70 nA) of an NMDA receptor blocker (5R-10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cycloheptene-5,10-imine hydrogen maleate (MK801) or a non-NMDA receptor blocker (6-cyano-7-nitroquinoxaline-2,3-dione) (CNQX), the mean number of spikes responding to the SSS stimulation significantly decreased (30, 50, and 70 nA; P < 0.05). These results suggest that there is a convergence of inputs from SSS and TP afferents on C1 neurons; it is possible that both NMDA and non-NMDA receptors located on C1 neurons may be targets for the treatment of the trigeminal referred pain associated with migraine.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Dental Pulp; Dizocilpine Maleate; Dura Mater; Electric Stimulation; Electromyography; Excitatory Amino Acid Antagonists; Iontophoresis; Male; Neck Muscles; Nociceptors; Pain, Referred; Posterior Horn Cells; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Toothache; Trigeminal Neuralgia

We have recently demonstrated that application of the mustard oil (MO), a small-fiber excitant and inflammatory irritant, to the rat maxillary molar tooth pulp induces significant increases in jaw muscle electromyographic (EMG) activity and neuroplastic changes in trigeminal (V) subnucleus caudalis. Since subnucleus oralis (Vo) as well as caudalis receives projections from molar pulp afferents and is also an integral brain stem relay of afferent input from orofacial structures, we tested whether MO application to the exposed pulp induces neuroplastic changes in oralis neurons and whether microinjection of MK-801, a noncompetitive NMDA antagonist, into the Vo influences the pulp/MO-induced neuroplastic changes in chloralose/urethan-anesthetized rats. Single neuronal activity was recorded in Vo, and neurons classified as low-threshold mechanoreceptive (LTM), wide dynamic range (WDR), nociceptive-specific (NS), deep (D), or skin/mucosa and deep (S + D). The spontaneous activity, mechanoreceptive field (RF) size, mechanical threshold, and response to suprathreshold mechanical stimuli applied to the neuronal RF were assessed prior to and throughout a 40- to 60-min period after MO application to the maxillary molar pulp. In animals pretreated with saline microinjection (0.3 microl) into the Vo, MO application to the pulp produced a significant increase in spontaneous activity, expansion of the pinch or deep RF, decrease in the mechanical threshold, and increase in response to suprathreshold mechanical stimuli of the nociceptive (WDR, NS, and S + D) neurons except for those nociceptive neurons having their RF only in the intraoral region. The pulpal application of MO did not produce any significant neuroplastic changes in LTM neurons. Furthermore, in animals pretreated with MK-801 microinjection (3 microg/0.3 microl) into the Vo, MO application to the pulp did not produce any significant changes in the RF and response properties of nociceptive neurons. In other animals pretreated with saline (0.3 microl) or MK-801 (3 microg/0.3 microl) microinjected into the Vo, mineral oil application to the pulp did not produce any significant changes in RF and response properties of nociceptive neurons. These findings indicate that the application of MO to the tooth pulp can induce significant neuroplastic changes in oralis nociceptive neurons and that central NMDA receptor mechanisms may be involved in these neuroplastic changes.

Topics: Animals; Brain Mapping; Dental Pulp; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Irritants; Male; Microelectrodes; Microinjections; Mustard Plant; Nerve Tissue Proteins; Neuronal Plasticity; Neurons, Afferent; Nociceptors; Pain Threshold; Plant Extracts; Plant Oils; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Toothache; Trigeminal Nuclei