Browsing by Author "Christie, MJ"

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    Analgesic ω-conotoxins CVIE and CVIF selectively and voltage-dependently block recombinant and native n-type calcium channels
    (American Society for Pharmacology and Experimental Therapeutics (ASPET), 2010-02-01) Berecki, G; Motin, L; Haythornthwaite, A; Vink, S; Bansal, PS; Drinkwater, R; Wang, CI; Moretta, M; Lewis, RJ; Alewood, PF; Christie, MJ; Adams, DJ
    Neuronal (N)-type Ca2+ channel-selective ω-conotoxins have emerged as potential new drugs for the treatment of chronic pain. In this study, two new ω-conotoxins, CVIE and CVIF, were discovered from a Conus catus cDNA library. Both conopeptides potently displaced 125I-GVIA binding to rat brain membranes. In Xenopus laevis oocytes, CVIE and CVIF potently and selectively inhibited depolarization-activated Ba2+ currents through recombinant N-type (α1B-b/α2δ1/β3) Ca2+ channels. Recovery from block increased with membrane hyperpolarization, indicating that CVIE and CVIF have a higher affinity for channels in the inactivated state. The link between inactivation and the reversibility of ω-conotoxin action was investigated by creating molecular diversity in β subunits: N-type channels with β2a subunits almost completely recovered from CVIE or CVIF block, whereas those with β3 subunits exhibited weak recovery, suggesting that reversibility of the ω-conotoxin block may depend on the type of β-subunit isoform. In rat dorsal root ganglion sensory neurons, neither peptide had an effect on low-voltage-activated T-type channels but potently and selectively inhibited high voltage-activated N-type Ca2+ channels in a voltage-dependent manner. In rat spinal cord slices, both peptides reversibly inhibited excitatory monosynaptic transmission between primary afferents and dorsal horn superficial lamina neurons. Homology models of CVIE and CVIF suggest that ω-conotoxin/voltage-gated Ca2+ channel interaction is dominated by ionic/electrostatic interactions. In the rat partial sciatic nerve ligation model of neuropathic pain, CVIE and CVIF (1 nM) significantly reduced allodynic behavior. These N-type Ca2+ channel-selective ω-conotoxins are therefore useful as neurophysiological tools and as potential therapeutic agents to inhibit nociceptive pain pathways. © 2010, American Society for Pharmacology and Experimental Therapeutics (ASPET)
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    Trishomocubanes: novel σ ligands modulate cocaine-induced behavioural effects
    (Elsevier Science B.V., 2007-01-19) Liu, X; Banister, SD; Christie, MJ; Banati, RB; Meikle, SR; Coster, MJ; Kassiou, M
    Trishomocubane analogues TC1 (N-(3′-fluorophenyl)ethyl-4-azahexacyclo [5.4.1.02,6.03,10.05,9.08,11]dodecan-3-ol) and TC4 (N-(3′-fluorophenyl)methyl-4-azahexacyclo [5.4.1.02,6.03,10.05,9.08,11]dodecan-3-ol) were evaluated for their modulatory effects on locomotor activity as well as interactions with cocaine-induced responses. TC1 and TC4 have high affinity and moderate to high selectivity for σ1 (Ki = 10 nM, σ1/σ2 = 0.03) and σ2 (Ki = 20 nM, σ1/σ2 = 7.6) receptor subtypes respectively. Both compounds have negligible affinity for the dopamine (DAT), serotonin (SERT), and norepinephrine (NET) transporters. In behavioural studies, TC1 produced a dose-related inhibition in spontaneous locomotor activity measured in a Digiscan apparatus. TC1 attenuated the stimulatory locomotor effect of 20 mg/kg cocaine with a half-maximal depressant activity (ID50) of 38.6 mg/kg. TC1 (dose range of 25 to 100 mg/kg) also partially substituted for the effect of cocaine (10 mg/kg) in a discriminative stimulus task, involving the trained discrimination between cocaine and saline using a two-lever choice method. Following a dose of 50 mg/kg TC1, a maximum of 31% substitution was reached. The response rate was reduced to 56% of vehicle control following a TC1 dose of 100 mg/kg. These behavioural effects suggest that TC1 can act as an antagonist via the σ1 receptor. In contrast to TC1, TC4 produced a stimulant effect in locomotor activity with the ED50 estimated at 0.94 mg/kg. In addition, TC4 failed to inhibit cocaine-induced stimulation; neither did it substitute for the discriminative stimulus effects of cocaine. TC4 thus appears to interact predominantly with the σ2 receptor subtype (σ1/σ2 = 7.6) which may result in dopamine stimulation independent of the effects of cocaine. The differential effect of TC1 and TC4 warrants further study of the mechanism of these actions. Present data also suggests a potential role for trishomocubane analogues in developing medication or research tools for cocaine addiction. © 2007, Elsevier Ltd.