Trigeminal neuralgia is an example of an extreme form of neuropathic pain and continues to be a real therapeutic challenge. Although the pathophysiology of the disorder is uncertain, vascular compression of the trigeminal root resulting in damage to primary afferent neurons is thought to play a major role in the generation of pain. In the present study, we have used a recently developed rat model of trigeminal neuropathic pain, where the neuropathy is produced by a chronic constriction injury of the infraorbital branch of the trigeminal nerve (CCI-ION), and for the first time studied the effects of various pharmacological treatments on this purely sensory model of neuropathic pain. Rats with a CCI-ION consistently display a series of spontaneous behavioural abnormalities that may be indicative of trigeminal paraesthesias/dysesthesias. A hyper-responsiveness of the territory of the ligated infraorbital nerve to light mechanical stimulation with von Frey hairs also develops at 7-12 days after the injury. Pharmacological studies indicated that the mechanical hyper-responsiveness could be reversibly abolished by local injections of alphacaine into the close proximity of the injured nerve. The allodynia-like behaviour was resistant to i.v. morphine. Similarly, single and repeated injections (using the respective T 1/2 as an interval) of tricyclic antidepressants amitriptyline and clomipramine were devoid of effects on the mechanical allodynia-like behaviour. Carbamazepine was effective only after doses (> or =10 mg/kg s.c.) that already caused disturbances in motor co-ordination in the rotarod test. Repeated injections of baclofen (3 mg/kg s.c.) partially alleviated the mechanical allodynia-like behaviour without effects on rotarod performance. The partial anti-allodynic effect of a single injection (5 mg/kg) of baclofen, which was already accompanied by slight motor disturbances, could be antagonized by CGP35348, a selective GABA(B)-receptor antagonist. Functional deficits in the GABAergic system may play an important role in the pathogenesis of this purely sensory rat model of trigeminal neuropathic pain.

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Within six months of the introduction of the new antipsychotic drug clozapine in Finalnd, 17 cases of neutropenia or agranulocytosis were recorded amongst about 3000 patients treated. Agranulocytosis was fatal in eight patients, and in addition, two patients developed thrombocytopenia, and one patient leukaemia. As additional cases might well have been overlooked as banal infections, the risk of developing agranulocytosis during clozapine treatment was at least 0.5%. Impaired elimination of the drug or increased susceptibility of granulocyte precursors to clozapine, possibly due to some inherited characteristic, might explain the high incidence of complications.

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