A5078372566- Pain Mechanisms and Treatments
- Neuroscience and Neuropharmacology Research
- Cannabis and Cannabinoid Research
- Neuropeptides and Animal Physiology
- Neurotransmitter Receptor Influence on Behavior
- Receptor Mechanisms and Signaling
- Urinary Bladder and Prostate Research
- Ion channel regulation and function
- Neuroscience of respiration and sleep
- Sleep and Wakefulness Research
- Pharmacological Receptor Mechanisms and Effects
- Nicotinic Acetylcholine Receptors Study
- Ion Channels and Receptors
- Olfactory and Sensory Function Studies
- Anesthesia and Pain Management
- Forensic Toxicology and Drug Analysis
- Epilepsy research and treatment
- Pelvic floor disorders treatments
- Veterinary Pharmacology and Anesthesia
- Thermal Regulation in Medicine
- Urinary Tract Infections Management
- Pediatric Pain Management Techniques
- Migraine and Headache Studies
- Inflammatory mediators and NSAID effects
- Veterinary Medicine and Surgery
The University of Sydney
2011-2024
Royal North Shore Hospital
2014-2023
Northern Sydney Local Health District
2003-2007
Institute of Pharmacology
2003
Fundación Juan March
2003
University College London
2000
University of London
1997
UNSW Sydney
1988
While cannabinoid receptor agonists have analgesic activity in chronic pain states, they produce a spectrum of central CB 1 receptor‐mediated motor and psychotropic side effects. The actions endocannabinoids, such as anandamide are terminated by removal from the extracellular space, then subsequent enzymatic degradation fatty‐acid amide hydrolase (FAAH). In present study, we compared effect selective FAAH inhibitor, URB597, to that pan‐cannabinoid agonist HU210 rat models inflammatory...
The midbrain periaqueductal gray (PAG) is a major site of cannabinoid-mediated analgesia in the central nervous system. In present study, we examined actions cannabinoids on rat PAG neurons vitro. brain slices, superfusion cannabinoid receptor agonist WIN55,212-2 inhibited electrically evoked inhibitory and excitatory postsynaptic currents all neurons. endogenous anandamide presence transport inhibitor AM404, but not its absence. stable analog R1-methanandamide also currents. reduced rate...
The actions of the endogenous ORL 1 ‐receptor (opioid receptor‐like ) ligand, nociceptin, on membrane properties rat dorsal raphe nucleus neurones were examined by use whole‐cell patch clamp recording in brain slices. Nociceptin produced an outward current all tested, with EC 50 12 ± 2 nM. Dynorphin A (100 nM to μ m little current. Outward currents reversed polarity near predicted K + equilibrium potential both 2.5 mM (measured/predicted = −105 mV/ −104 mV) and 6.5 −80 −77 extracellular ....
1. The actions of opioids on synaptic transmission in rat periaqueductal grey (PAG) neurones were examined using whole‐cell patch‐clamp recordings brain slices. 2. Methionine enkephalin (ME; 10 microM) inhibited evoked GABAergic inhibitory postsynaptic currents (IPSCs) by 57%, non‐NMDA excitatory (EPSCs) 60%, and NMDA EPSCs 43% PAG neurones. This inhibition was associated with an increase paired‐pulse facilitation, mimicked the mu‐agonist DAMGO (1‐3 abolished naloxone (1 microM). Neither...
In this study we have examined the effects of nociceptin, an endogenous ligand for opioid‐like receptor ORL 1 , on membrane properties rat locus coeruleus (LC) neurones in vitro using intracellular and whole cell patch clamp recording. When were voltage clamped to −60 mV, application nociceptin caused outward current all cells ( n = 49), with EC 50 90 nM. Neither potency nor maximal effect was altered presence peptidase inhibitors, bestatin (20 μ m ) or thiorphan (2 ). The currents by 2.5 mM...
The tetrodotoxin-resistant voltage-gated sodium channel (VGSC) Na(v)1.8 is expressed predominantly by damage-sensing primary afferent nerves and important for the development maintenance of persistent pain states. Here we demonstrate that muO-conotoxin MrVIB from Conus marmoreus displays substantial selectivity inhibits behavior in models pain. In rat sensory neurons, submicromolar concentrations blocked current characteristic but not Na(v)1.9 or tetrodotoxin-sensitive VGSC currents. human...
Chronic morphine administration induces adaptations in neurons resulting opioid tolerance and dependence. Functional studies have implicated a role for the periaqueductal gray area (PAG) expression of many signs withdrawal, but cellular mechanisms are not fully understood. This study describes an increased efficacy, rather than tolerance, agonists at μ-receptors on GABAergic (but glutamatergic) nerve terminals PAG after chronic treatment. Opioid withdrawal enhanced amplitudes electrically...
The vanilloid receptor protein (VR1) is a well-characterised integrator of noxious stimuli in peripheral sensory neurones. There evidence for the presence VR1 central nervous system, but little information as to its role there. In this study we have examined actions agonists receptors rat locus coeruleus (LC), using whole-cell patch-clamp recordings from acutely isolated neurones and slices. Superfusion with capsaicin resulted concentration-dependent increase frequency miniature excitatory...
The actions of the endogenous ORL 1 -receptor ligand nociceptin on membrane properties and synaptic currents in rat periaqueductal gray (PAG) neurons were examined by use whole-cell patch-clamp recording brain slices. Nociceptin produced an outward current all tested, with EC 50 39 ± 7 n m . was unaffected naloxone. Outward reversed polarity at −110 3 mV 2.5 extracellular potassium, reversal potential increased when potassium concentration raised (slope = 66.3 mV/log[K + ] o ). Thus,...
The rostral ventromedial medulla (RVM) is thought to play a crucial role in the antinociceptive actions of cannabinoids. This study examined cannabinoid receptor agonist, WIN55,212‐2, on membrane properties and GABAergic synaptic transmission RVM neurons using whole cell patch clamp recordings brain slices. WIN55,212‐2 (3 μ M ) had no effect K + conductance primary or secondary neurons. Primary responded κ‐opioid agonist U69,593 (300 n –1 ). Secondary μ,δ‐opioid met‐enkephalin (10 reduced...
1. Rat caudal periaqueductal grey (PAG) output neurones containing rhodamine microspheres, retrogradely transported from an injection site in the rostral ventromedial medulla (RVM), were visualized brain slices and recorded using whole‐cell patch clamp techniques. 2. The specific GABAB receptor agonist baclofen (10 microM) produced outward current or hyperpolarization fifty out of fifty‐six PAG neurones. In 44% these baclofen‐sensitive neurones, opioid methionine enkephalin (30 also...
Abstract Cannabis and its psychoactive constituent Δ9-tetrahydrocannabinol (THC) have efficacy against neuropathic pain, however, this is hampered by their side effects. It has been suggested that co-administration with another major cannabidiol (CBD) might enhance the analgesic actions of THC minimise deleterious We examined basis for phytocannabinoid interaction in a mouse chronic constriction injury (CCI) model pain. Acute systemic administration dose-dependently reduced CCI-induced...
Background and Purpose Clinical studies have reported that pan‐cannabinoid receptor agonists may efficacy in neuropathic pain states this might be enhanced by co‐administration with opioids. While cannabinoid–opioid analgesic synergy has been demonstrated animal models of acute pain, it not examined models. We the effect combination treatment cannabinoid opioid on allodynia side effects a nerve injury‐induced model. Experimental Approach C57BL/6 mice were subjected to chronic constriction...
Calcium (Ca2+)-permeable AMPA receptors may, in certain circumstances, contribute to normal synaptic plasticity or neurodegeneration. are Ca2+-permeable if they lack the GluA2 subunit is unedited at a single nucleic acid, known as Q/R site. In this study, we examined mice engineered with point mutation intronic editing complementary sequence (ECS) of gene, Gria2. Mice heterozygous for ECS (named GluA2+/ECS(G)) had ~ 20% reduction RNA We conducted an initial phenotypic analysis these mice,...
The rostral ventromedial medulla (RVM) forms part of a descending pathway that modulates nociceptive neurotransmission at the level spinal cord dorsal horn. However, involvement RVM systems in opioid analgesia are matter some debate. In present study, patch-clamp recordings neurons were made from rats had received retrograde tracer injections into cord. More than 90% identified spinally projecting responded to agonists. Of these neurons, 53% only mu-opioid agonist D-Ala2, N-Me-Phe4, Gly-ol5...
α-Conotoxins that are thought to act as antagonists of nicotinic acetylcholine receptors (nAChRs) containing α3-subunits efficacious in several preclinical models chronic pain. Potent interactions Vc1.1 with other targets have suggested the pain-relieving actions α-conotoxins might be mediated by either α9α10 nAChRs or a novel GABAB receptor-mediated inhibition N-type calcium channels. Here we establish three α-conotoxins, Vc1.1, AuIB and MII distinct selectivity profiles for these potential...