1. The effects of the TRPV1 receptor antagonist SB-705498 on trigeminovascular sensitisation and neurotransmission.
- Author
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Lambert GA, Davis JB, Appleby JM, Chizh BA, Hoskin KL, and Zagami AS
- Subjects
- Analgesics administration & dosage, Analgesics blood, Animals, Blood Pressure drug effects, Cats, Cerebrovascular Circulation drug effects, Disease Models, Animal, Electric Stimulation, Evoked Potentials, Face, Inflammation metabolism, Inflammation physiopathology, Inflammation Mediators metabolism, Injections, Intravenous, Migraine Disorders metabolism, Migraine Disorders physiopathology, Nerve Fibers, Myelinated drug effects, Nerve Fibers, Myelinated metabolism, Pain metabolism, Pain physiopathology, Pain Measurement, Pain Threshold drug effects, Pyrrolidines administration & dosage, Pyrrolidines blood, Reaction Time drug effects, TRPV Cation Channels metabolism, Time Factors, Trigeminal Caudal Nucleus drug effects, Trigeminal Caudal Nucleus metabolism, Trigeminal Caudal Nucleus physiopathology, Trigeminal Nerve metabolism, Trigeminal Nerve physiopathology, Urea administration & dosage, Urea blood, Urea pharmacology, Analgesics pharmacology, Dura Mater blood supply, Inflammation drug therapy, Migraine Disorders drug therapy, Pain drug therapy, Pyrrolidines pharmacology, Skin innervation, Synaptic Transmission drug effects, TRPV Cation Channels antagonists & inhibitors, Trigeminal Nerve drug effects, Urea analogs & derivatives
- Abstract
This report examines the effect of the transient receptor potential vanilloid 1 receptor antagonist SB-705498 on neurotransmission and inflammation-induced sensitisation in the trigeminovascular sensory system. A single-neuron electrophysiological animal model for neurovascular head pain was used to evaluate dural and facial noxious inputs and the effects of SB-705498 administered by intravenous (i.v.) injection. Electrical and mechanical stimulation of the dura mater and the facial skin activated second-order neurons in the trigeminal nucleus caudalis of cats, with A-delta latencies. Intravenous injection of SB-705498 (2 mg kg(-1)) produced a slowly developing and long-lasting suppression of responses to dural and skin stimulation. Maximum suppression occurred by 1 h and reached 41% for dura and 24% for skin. Intravenous injection of drug vehicle did not produce significant suppression of responses to stimulation of either dura or skin. Intravenous injection of SB-705498 produced a brief and small rise in blood pressure and dural blood flow, which both returned to normal before suppression of the responses to stimulation became manifest. Application of "inflammatory soup" to the dura mater produced a pronounced increase in dural blood flow and induced a slowly developing increase in the responses of neurons to both electrical and mechanical stimulations of their facial and dural receptive fields. This sensitisation reached a maximum in 60-90 min, at which time responses had risen to approximately twice that of control levels seen before the application of inflammatory soup. Intravenous injection of SB-705498 subsequent to the development of sensitisation produced a slowly developing, prolonged and statistically significant reversal of the sensitisation induced by inflammatory soup. Maximum reversal of sensitisation to electrical stimulation occurred by 150-180 min, when responses had fallen to, or below, control levels. At 70-85 min following injection of SB-705498, the responses of previously sensitised neurons to mechanical stimulation of dura mater and facial receptive field had also returned to near control levels. SB-705498 was also able to prevent the development of sensitisation; application of inflammatory soup to the dura mater induced a slowly developing increase in the responses of neurons to electrical stimulation of the skin and dura mater in cats which had received an i.v. injection of vehicle for SB-705498 but not in cats which had received the active drug. Blood levels of SB-705498 were maximal immediately following i.v. injection and declined over the following 2 h. Significant brain levels of SB-705498 were maintained for up to 9 h. These results suggest that SB-705498 may be an effective suppressant and reversal agent of the sensitisation to sensory input which follows inflammation in the trigeminovascular sensory distribution but may not be particularly useful in blocking primary pain processes such as migraine headache. SB-705498 could thus potentially prevent, modify or reverse the cutaneous trigeminal allodynia seen in certain migraine conditions, especially "transformed" migraine.
- Published
- 2009
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