Synergistic effect of combining dual enkephalinase inhibitor PL37 and sumatriptan in a preclinical model of migraine.

Objective: The aim of this study was to test whether a combination of sumatriptan with dual enkephalinase inhibitor PL37 would result in an additive or a synergistic effect.

Background: Combination treatment is frequently used to improve the therapeutic efficacy of drugs. The co-administration of two drugs may result in efficacy at lower doses than those needed for either drug alone, thus minimizing side effects.

Dual enkephalinase inhibitor PL37 as a potential novel treatment of migraine: evidence from a rat model.

The dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from rapid degradation, has demonstrated analgesic properties in animal pain models and in early human clinical trials. This study tested the antimigraine potential of PL37 on cutaneous mechanical hypersensitivity affecting cephalic regions in migraineurs. Using behavioural testing and c-Fos immunoreactivity in male rats, we investigated the effects of single (oral or intravenous) and repeated oral administration of PL37 on changes in cutaneous mechanical sensitivity and sensitization of the trigeminocervical complex induced by repeated administration of the nitric oxide donor, isosorbide dinitrate.

Model-based signal processing enables bidirectional inferring between local field potential and spikes evoked by noxious stimulation.

Background: Recording spontaneous and evoked activities by means of unitary extracellular recordings and local field potential (LFP) are key understanding the mechanisms of neural coding. The LFP is one of the most popular and easy methods to measure the activity of a population of neurons. LFP is also a composite signal known to be difficult to interpret and model.

Recurrent administration of the nitric oxide donor, isosorbide dinitrate, induces a persistent cephalic cutaneous hypersensitivity: A model for migraine progression.

Background A subgroup of migraineurs experience an increase in attack frequency leading to chronic migraine. Methods We assessed in rats the roles of dose and repeat administration of systemic isosorbide dinitrate (ISDN), a nitric oxide donor, on the occurrence and development of cephalic/face and extracephalic/hindpaw mechanical allodynia as a surrogate of migraine pain, and the effect of acute systemic sumatriptan and olcegepant and chronic systemic propranolol on these behavioral changes. Results A single high (H-ISDN) but not low (L-ISDN) dose of ISDN induces a reversible cephalic and extracephalic mechanical allodynia.

The nitric oxide donor, isosorbide dinitrate, induces a cephalic cutaneous hypersensitivity, associated with sensitization of the medullary dorsal horn.

Nitric oxide donors are known to produce headache in healthy as well as migraine subjects, and to induce extracephalic cutaneous hypersensitivity in rodents. However, little is known on the effect of nitric oxide donors on cephalic cutaneous sensitivity. Combining behavioral, immunohistochemical, and in vivo electrophysiological approaches, this study investigated the effect of systemic administration of the nitric oxide donor, isosorbide dinitrate (ISDN), on cephalic and extracephalic cutaneous sensitivity and on neuronal activation within the medullary dorsal horn (MDH) in the rat.

GABAAergic inhibition or dopamine denervation of the A11 hypothalamic nucleus induces trigeminal analgesia.

Descending pain-modulatory systems, either inhibitory or facilitatory, play a critical role in both acute and chronic pain. Compared with serotonin and norepinephrine, little is known about the function of dopamine (DA). We characterized the anatomical organization of descending DA pathways from hypothalamic A11 nuclei to the medullary dorsal horn (MDH) and investigated their role in trigeminal pain.

The nucleus raphe magnus OFF-cells are involved in diffuse noxious inhibitory controls.

Diffuse noxious inhibitory controls (DNIC) are very powerful long-lasting descending inhibitory controls which are pivotal in modulating the activity of spinal and trigeminal nociceptive neurons. DNIC are subserved by a loop involving supraspinal structures such as the lateral parabrachial nucleus and the subnucleus reticularis dorsalis. Surprisingly, though, whether the nucleus raphe magnus (NRM), another supraspinal area which is long known to be important in pain modulation, is involved in DNIC is still a matter of discussion.

Correction: Bilateral Descending Hypothalamic Projections to the Spinal Trigeminal Nucleus Caudalis in Rats.

[This corrects the article on p. e73022 in vol. 8.

Bilateral descending hypothalamic projections to the spinal trigeminal nucleus caudalis in rats.

Several lines of evidence suggest that the hypothalamus is involved in trigeminal pain processing. However, the organization of descending hypothalamic projections to the spinal trigeminal nucleus caudalis (Sp5C) remains poorly understood. Microinjections of the retrograde tracer, fluorogold (FG), into the Sp5C, in rats, reveal that five hypothalamic nuclei project to the Sp5C: the paraventricular nucleus, the lateral hypothalamic area, the perifornical hypothalamic area, the A11 nucleus and the retrochiasmatic area.

Spinal μ and δ opioids inhibit both thermal and mechanical pain in rats.

The expression and contribution of μ (MOPR) and δ opioid receptors (DOPR) in polymodal nociceptors have been recently challenged. Indeed, MOPR and DOPR were shown to be expressed in distinct subpopulation of nociceptors where they inhibit pain induced by noxious heat and mechanical stimuli, respectively. In the present study, we used electrophysiological measurements to assess the effect of spinal MOPR and DOPR activation on heat-induced and mechanically induced diffuse noxious inhibitory controls (DNICs).

Tonic and phasic descending dopaminergic controls of nociceptive transmission in the medullary dorsal horn.

The transfer of nociceptive information at the level of dorsal horn is subject to extensive processing by both local segmental and supraspinal mechanisms, including descending dopaminergic controls, originating from the hypothalamic A11 nucleus. The inhibitory role of dopamine on evoked pain via activation of D2-like receptors at the level of the dorsal horn is well established. Here, by use of behavioral, electrophysiological, and anatomical techniques, we examined within the trigeminal sensory complex, first, whether descending dopaminergic controls also modulate pain behavior after an inflammatory insult, and second, under which physiological conditions these descending dopaminergic controls are actually recruited.

NK1 receptor-expressing spinoparabrachial neurons trigger diffuse noxious inhibitory controls through lateral parabrachial activation in the male rat.

Diffuse noxious inhibitory controls (DNIC) are very powerful long-lasting descending inhibitory controls, which are pivotal in modulating the activity of spinal and trigeminal nociceptive neurons. The principal feature of DNIC is that they are subserved by a loop that involves supraspinal structures that have not yet been identified. Using behavioral, in vivo extracellular electrophysiological and anatomical approaches, we studied the neuronal network underlying DNIC.

A role for wind-up in trigeminal sensory processing: intensity coding of nociceptive stimuli in the rat.

Wind-up is a progressive, frequency-dependent increase in the excitability of trigeminal and spinal dorsal horn wide dynamic range (WDR) nociceptive neurons evoked by repetitive stimulation of primary afferent nociceptive C-fibres. The correlate of wind-up in humans is temporal summation, which is an increase in pain perception to repetitive constant nociceptive stimulation. Although wind-up is widely used as a tool for studying the processing of nociceptive information, including central sensitization, its actual role is still unknown.

Dorsal horn NK1-expressing neurons control windup of downstream trigeminal nociceptive neurons.

Windup is a progressive, frequency-dependent increase in the excitability of trigeminal and spinal dorsal horn wide dynamic range (WDR) nociceptive neurons to repetitive stimulation of primary afferent nociceptive C-fibers. Superficial dorsal horn neurokinin 1 receptor (NK1R)-expressing neurons were recently shown to regulate sensitization of WDR nociceptive neurons through activation of a defined spino-bulbo-spinal loop. However, the windup of WDR nociceptive neurons was not regulated through this loop.

The orofacial formalin test in the mouse: a behavioral model for studying physiology and modulation of trigeminal nociception.

Unlabelled: The aim of the current study was to adapt the orofacial formalin pain model previously developed in rats for use in mice and to characterize as fully as possible the behavioral changes in this species. The effects of subcutaneous injection of different formalin concentrations (.5%, 1%, 2%, 4%, and 8%) were examined on the face-rubbing response.

Synergistic antinociceptive effect of amitriptyline and morphine in the rat orofacial formalin test.

Background: Combination therapy is often used to increase the clinical utility of analgesic agents. The coadministration of two compounds may achieve analgesia at doses lower than those required for either compound alone, leading to enhanced pain relief and reduction of adverse effects. Herein, the authors describe the effect of coadministration of morphine and amitriptyline on cutaneous orofacial inflammatory pain in rats.

Bidirectional modulation of windup by NMDA receptors in the rat spinal trigeminal nucleus.

Activation of afferent nociceptive pathways is subject to activity-dependent plasticity, which may manifest as windup, a progressive increase in the response of dorsal horn nociceptive neurons to repeated stimuli. At the cellular level, N-methyl-d-aspartate (NMDA) receptor activation by glutamate released from nociceptive C-afferent terminals is currently thought to generate windup. Most of the wide dynamic range nociceptive neurons that display windup, however, do not receive direct C-fibre input.

Contribution of neurokinin 1 receptors in the cutaneous orofacial inflammatory pain.

This study investigated the role of neurokinin 1 receptors (NK1R) in inflammatory cutaneous orofacial pain. The effects of subcutaneous and intracisternal administration of the NK1R antagonist SR140333 on the face rubbing response provoked by injection of 50 micro l of 1.5% formalin into the vibrissa pad were examined.

Low doses of N-methyl-D-aspartate antagonists in superficial laminae of medulla oblongata facilitate wind-up of convergent neurones.

In this study, a trigeminal model was used in which high threshold C-fibre-evoked activities of convergent neurones located in the subnucleus oralis of the trigeminal complex are modulated through the superficial part, the substantia gelatinosa, of the subnucleus caudalis. The two subnuclei are located 3 mm apart, therefore, it was possible to inject dizocilpine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, into either the superficial or the deep parts of subnucleus caudalis without interfering with ongoing recording of convergent neurones in subnucleus oralis. A differential NMDA-dependent modulation of wind-up was observed according to the dose and the injection target.

Superficial and deep convergent nociceptive neurons are differentially affected by N-methyl-D-aspartate applied on the brainstem surface of the rat medullary dorsal horn.

The activation of N-methyl-D-aspartate receptors is implicated in the spinal and trigeminal processing of nociceptive information conveyed by convergent (wide dynamic range) neurons and particularly in C-fiber-evoked responses elicited by repetitive and high-intensity electrical stimulation of the neuronal receptive field. In this study, the effects of intrathecal NMDA application on the electrically evoked nociceptive responses of trigeminal subnucleus caudalis convergent neurons have been investigated. The total C-fiber-evoked activity triggered by 30 successive stimuli was divided into two components: the C-fiber input response and the 'wind-up' response.

Stimulus-function, wind-up and modulation by diffuse noxious inhibitory controls of responses of convergent neurons of the spinal trigeminal nucleus oralis.

Extracellular unitary recordings were made from 53 spinal trigeminal nucleus oralis (Sp5O) convergent neurons in halothane-anaesthetized rats. The neurons had an ipsilateral receptive field including mainly oral or perioral regions. They responded to percutaneous electrical stimulation with two peaks of activation.

Effects of lesions in the trigeminal oralis and caudalis subnuclei on different orofacial nociceptive responses in the rat.

Behavioural responses to two different orofacial noxious stimulations were analysed following lesion of spinal trigeminal subnucleus oralis (Sp5O) in the rat. Lesions were obtained by intranuclear microinjections of quinolinic acid (0.4 microliter of 60 nmol/microliter solution).

Effect of an NMDA receptor antagonist on the wind-up of neurons in the trigeminal oralis subnucleus.

Extracellular recordings of convergent neurons of the oralis subnucleus of the trigeminal sensory complex were performed in paralysed rats under halothane-N2O-O2 anesthesia using glass micropipettes. The effects of MK801, a noncompetitive NMDA receptor antagonist, were observed on the increased cell activity (wind-up), triggered by the repetition, at a low frequency (0.66 Hz) and high intensity (3 times the threshold of C-fiber response), of electrical stimulation of the receptive field.

Effects of morphine microinjections into the trigeminal sensory complex on the formalin test in the rat.

The aim of this study was to find out whether morphine locally applied into the different subnuclei of the spinal trigeminal nucleus could impair the behavioral response evoked by a tonic nociceptive stimulus. Microinjections of morphine were performed unilaterally in rats through a chronically implanted tube. The duration of the formalin-induced biphasic rubbing activity was used as a measure of nociception.

Effects of systemic morphine on the activity of convergent neurons of spinal trigeminal nucleus oralis in the rat.

The spinal trigeminal nucleus oralis has been shown to relay nociceptive inputs mainly from the oral and perioral regions. In this study, we examined the effects of intravenous administration of morphine on C-fiber-evoked activities of spinal trigeminal nucleus oralis convergent neurons in halothane-anesthetized rats. Morphine depressed the C-fiber-evoked responses of spinal trigeminal nucleus oralis convergent neurons in a dose-related (3-12 mg/kg range) and naloxone-reversible fashion.