Brian Cairns

Professor

Faculty of Pharmaceutical Sciences

Research Classification

Neurosciences, biological and chemical aspects

Neurosciences, medical and physiological and health aspects

Pharmacology and pharmaceutical sciences (except clinical aspects)

Research Interests

electrophysiology

headache

Neuropharmacology

Oro-Facial Pain

pain

pain mechanisms

peripheral analgesics

sex-related differences

temporomandibular disorders

Relevant Thesis-Based Degree Programs

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Affiliations to Research Centres, Institutes & Clusters

Centre for Brain Health

Research Options

I am available and interested in collaborations (e.g. clusters, grants).

I am interested in and conduct interdisciplinary research.

Graduate Student Supervision

Doctoral Student Supervision

Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

A novel preclinical model of migraine : systemic monosodium glutamate administration (2022)

Consumption of Monosodium Glutamate (MSG) in healthy people provokes headache, nausea and craniofacial tenderness that mimics that of an acute migraine attack in migraineurs. I hypothesize that systemic administration of MSG produces behavioural signs of headache, nausea and craniofacial tenderness through the activation of peripheral N-methyl-d-aspartate (NMDA) receptors in rats. The behavior of male and female Sprague Dawley rats was video recorded before and after intraperitoneal (i.p.) injections of either MSG (1-1000 mg/kg), nitroglycerin (GTN, 10 mg/kg) or normal saline. Behaviors (grimace score, head-flicks, rearing, head scratches, facial grooming, lying-on-belly, and temporalis muscle region mechanical withdrawal threshold (MT)) were evaluated. Facial cutaneous temperature of the nose and forehead was measured before and after i.p. injections via infrared thermography. Plasma glutamate and calcitonin-gene related peptide (CGRP) concentrations after administration of 1000 mg/kg MSG were measured in anesthetized rats. MSG induced headache- and nausea-like behaviors in a dose-related manner but had no effect on MT. MSG (1000 mg/kg) induced a significantly greater frequency of headache-like behavior in females, but a longer duration of nausea-like behavior in males. MSG produced a prolonged increase in plasma glutamate and CGRP concentrations. Co-administration of the median effective dose of MSG (350 mg/kg) with GTN (10 mg/kg) amplified headache-like behaviors, induced significant craniofacial sensitivity, and increased nausea-like behaviour. Co-administration of anti-migraine (sumatriptan and naproxen), anti-nausea (ondansetron and metoclopramide) drugs with MSG (1000 mg/kg) significantly attenuated MSG-induced headache and nausea-like behaviours respectively. Co-administration of the selective NMDA receptor antagonist 2R-amino-5-phosphonovaleric acid (APV 50 mg/kg), the non-NMDA receptor antagonist kynurenic acid (KYN 1 – 100 mg/kg) and the CGRP receptor antagonist (olcegepant 1 mg/kg), reduced headache-like behaviors evoked by MSG (1000 mg/kg). Only olcegepant when co-administered with MSG attenuated MSG-induced nausea-like behaviours. No alteration in motor function was observed by APV, KYN or olcegepant in rotarod experiments. My results suggest that systemic administration of MSG to rats induces behavioral correlates of headache and nausea that are mediated in part through peripheral NMDA receptor activation. Thus, systemic administration of MSG to rats may be used as a preclinical model for development and pre-clinical testing of new therapeutic targets in migraine.

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The Role of Peripheral NMDA Receptors in Nerve Growth Factor-Induced Muscle Pain (2015)

Intramuscular injections of nerve growth factor (NGF) into human masseter muscle induce a local mechanical sensitization that mimics the symptoms of myofascial pain in patients with temporomandibular disorders. I hypothesize that NGF induces the myofascial mechanical sensitization in part by increasing the expression of N-methyl-D-aspartate (NMDA) receptors in primary afferent neurons. In behavioral experiments, injection of NGF into rat masseter muscle induced a prolonged local mechanical sensitization that was greater in female rats than in male rats. This NGF-induced sensitization was partly attenuated by a local injection of the NMDA receptor antagonist APV at 3 days post NGF injection in the male rats but not in the female rats. Immunohistochemical studies found that this NGF-induced mechanical sensitization was accompanied by the increased expression of NMDA receptor subtype 2B (NR2B) in trigeminal ganglion neurons innervating the masseter muscle in both sexes, as well as an increase in the average soma size of NR2B-expressing neurons. An increase in the expression of neuropeptides (CGRP/SP) was also observed in the female rats but not in the male rats. In in vivo extracellular recordings of masseter trigeminal ganglion neurons, NGF increased NMDA-induced mechanical sensitization in the male rats but not in the female rats. However, in the female rats, this effect was greater in slow Aδ fibers (2-7 m/s) than fast Aδ fibers (>7-12 m/s). My results suggest that NGF-induced mechanical sensitization is mediated, in part, through an effect on peripheral NMDA receptors in a sexually dimorphic manner.

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Tumor necrosis factor alpha and non-inflammatory sensitization of masseter muscle nociceptors (2011)

Behavioral evidence in rats indicates that injection of tumor necrosis factor alpha (TNFalpha into skeletal muscle results in a prolonged mechanical sensitization without gross inflammation. The present series of studies were conducted to test the idea that injection of TNFalpha causes mechanical sensitization of skeletal muscle through a peripheral mechanism that involves lowering of the mechanical threshold (MT) of muscle nociceptors without inflammation. In- vivo extracellular electrophysiological recording was used to assess the effect of TNFalpha (1 or 0.1microgram) and other drugs on the excitability and MT of masseter muscle nociceptors. Expression of TNFR1 (P55) and TNFR2 (P75) receptors by the masseter muscle and trigeminal ganglion neurons that innervate that muscle was determined by Western blot and immunohistochemical methodologies, respectively. The Evans blue dye technique and thermal camera recordings were used to assess inflammation in muscle tissues. Enzyme-linked immunoassays and glutamate biosensor probes were used to measure muscle concentrations of prostaglandin (PG) E2 and nerve growth factor, and glutamate, respectively. Intramuscular injection of 1mg TNFalpha did not excite nociceptors, but did significantly decrease MT compared to vehicle control. There was no evidence of gross inflammation 3 hours after injection of TNFalpha. Co-injection of TNFalpha with P55 or P75 receptor antibodies attenuated TNFalpha-induced mechanical sensitization. P55 and P75 receptors were expressed by 29% and 62% of masseter nociceptors, respectively. PGE2 and glutamate concentrations were significantly changed 3 hours after TNFalpha injection into the masseter muscle. Injection of diclofenac, a cycloxygenase inhibitor that attenuates prostaglandin synthesis, partially reversed the TNFalpha-induced decreases in the MT of masseter muscle nociceptors, while vehicle control, DL-2-amino-5-phophonovaleric acid, a competitive NMDA receptor antagonist, and a tyrosine kinase A receptor antibody, which blocks NGF-induced masseter muscle nociceptor sensitization, did not significantly alter nociceptor MT. These findings indicate that TNFalpha-induced mechanical sensitization of masseter nociceptors is mediated, in part, by increased PGE2 levels through activation of peripheral P55 and P75 receptors. Over all, these results suggest that injection of TNFalpha into skeletal muscle could be used as a model of myofascial trigger points to study the peripheral pain mechanisms of masticatory muscle pain.

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Master's Student Supervision

Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

The effect of intraganglionic injection of GABA and GABA agonists on peripheral sensory transmission (2021)

Due to the lack of chemical synapses in the trigeminal ganglion, it is widely believed that it does not play a role in transmission of sensory signals. However, it has been shown that neurons and satellite glial cells in trigeminal ganglion express neuroreceptors such as γ-aminobutyric acid (GABA)A and GABAB receptors and can release neurotransmitters like GABA. Increasing the levels of GABA in the trigeminal ganglion was showed to have anti-nociceptive effects, while blockade of GABA receptor expression in the trigeminal ganglion was demonstrated to increase pain behaviors. However, the neuronal mechanism underlying these effects remains to be examined. In the current study, the expression of GABA receptors in the trigeminal ganglion neurons that innervate labial skin and masseter muscle was evaluated by immunohistochemistry. Using single unit recording, trigeminal brainstem and ganglion neuron responses to stimulation of labial skin and/or masseter muscle were evaluated after intraganglionic injections of GABA receptor agonists in rats. The mean frequency of expression of GABAA and GABAB receptors by masseter and labial skin ganglion neurons was 62.5% and 92.7%, and 55.4% and 20.3%, respectively. In both skin and muscle ganglion neurons, the expression of GABAA was higher than GABAB. There was a higher frequency of GABAA as well as GABAB receptor expression in ganglion neurons that innervated the skin compared with those that innervated muscle. In ganglion neurons that innervated the skin, there was a higher expression of GABAA receptors and GABAB receptors in males compared to females. Masticatory muscle evoked brainstem trigeminal neuron responses were attenuated by intraganglionic injection of muscimol (GABAA), but not baclofen (GABAB). Compared to Phosphate Buffered Saline (PBS), all substances reduced mechanical threshold 30 minutes post injection. Further, GABA (500 mM) and baclofen 10 mM decreased mechanical threshold (MT) compared to PBS for the entire recording period. All these changes were statistically significant. The mechanical sensitivity of slow and fast conducting masticatory muscle afferent fibers was decreased and increased, respectively, by intraganglionic injection of both muscimol and baclofen. This study suggests that activation of peripheral GABA receptors may exert a selective gating effect on sensory input passing through trigeminal ganglion.

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The role of monosodium glutamate in headache (2016)

Consumption of monosodium glutamate (MSG) can induce headache in young healthy individuals and migraine-like headache in migraineurs. Blood plasma levels of glutamate are also elevated in migraineurs, but it is unknown how elevated levels of glutamate contribute to headache. The current study was undertaken to investigate the hypothesis that monosodium glutamate induces headache through activation of peripheral glutamate receptors. To test the hypothesis, we combined in vivo electrophysiology, laser Doppler recordings of dural vasculature, and immunohistochemistry to investigate the effect of systemic administration of MSG on the trigeminovascular pathway. Immunohistochemical analysis of the dura, determined that the nerve fibres innervating dural blood vessels express NMDA, AMPA, kainate and mGlur5 receptors. The glutamate transporter EAAT2, but not EAAT1 or 3, is expressed by dural blood vessels. Systemic administration of 50mg/kg MSG induced a 24.5 and 20.6 percent increase in dural blood flow in male and female rats, respectively, as measured by laser Doppler flowmetry. Dural blood flow returned to baseline values by a mean of 170 seconds. In in vivo extracellular recordings of spinal trigeminal subnucleus caudalis (SpVc) neurons with dural receptive fields, intravenously administered MSG evoked an increase in neuronal discharge in 5/6 neurons in both male and female rats. MSG also induced mechanical sensitization in both sexes. When the NMDA receptor selective antagonist APV (5, 50mg/kg) was co-administered with MSG, it attenuated both the MSG evoked activation and mechanical sensitization of SpVc neurons. Myresults suggest that MSG induced headache is mediated, in part, through activation of the peripheral NMDA receptor.

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An animal model of Burning Mouth Syndrome (BMS) for assessment of peripheral Gamma-Aminobutyric Acid A (GABBA) receptors as an analgesic target (2013)

Burning Mouth Syndrome (BMS) is a chronic pain syndrome characterised byburning pain in patients with clinically normal oral mucosa (Grushka et al., 2002). Theprevalence of BMS increases with age and occurs far more commonly in women, withestimated female to male ratios ranging from 3:1 to 16:1 (Grushka, 1987b, van der Ploeg etal., 1987, Clark G.T, 2005). In women, there is a strong correlation between the developmentof BMS and the onset of menopause (Lipton et al., 1993, Bergdahl and Bergdahl, 1999). Aproposed theory is that deprivation of oestrogen produces atrophic changes within the oralepithelium (Valimaa et al., 2004) leading to symptoms of BMS. Therefore, I employedimmunohistochemistry and electrophysiology techniques to test the hypotheses thatovariectomised rats will show reduced nerve fibre densities and lower proportions ofpeptidergic neuronal fibres (small-diameter fibres) in the tongues leading to reducedthermal and mechanical thresholds of afferent fibres. A non-conventional treatment forBMS that seems effective (Gremeau-Richard et al., 2004) is sucking a tablet of thebenzodiazepine (BZD), clonazepam, without swallowing. This treatment is speculated todecrease pain by activating peripheral ɣ-aminobutyric acid receptors A (GABAA) receptorsin the oral cavity. Expression of GABAA receptors in tongue afferent fibres has yet to bedemonstrated. Also, evidence for a direct effect of BZDs on nociceptors in the oral mucosais lacking. My hypotheses are: GABAA receptors are present on both peptidergic andnon-peptidergic nerve fibres. Activation of peripheral GABAA receptors will increasemechanical thresholds of tongue nerve fibres which would explain the therapeutic efficacyof topical clonazepam in human BMS. This study found high proportions of GABAAʏ²-containing, peptidergic (94%) and GABAAʏ²-containing, non-peptidergic (93%) tongueaxonal fibres of intact female rats. In intact females, muscimol and ɣ-aminobutyric acid (GABA) solutions had no effect on relative mechanical thresholds of afferent fibres. After thermal stimulation, muscimol significantly increased relative mechanical thresholds of afferent fibres. Ovariectomised and sham-operated rats did not differ in any of the parameters measured. Topical applications of muscimol and bicuculline solutions did not have any significant effect on relative mechanical thresholds of nerve fibres in both rat groups.

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