The antimigraine 5-HT_(1B/1D) receptor agonists, sumatriptan, zolmitriptan and dihydroergotamine, attenuate pain-related behaviour in a rat model of trigeminal neuropathic pain

摘要

1. Peripheral lesion to the trigeminal nerve may induce severe pain states. Several lines of evidence have suggested that the antimigraine effect of the triptans with 5-HT_(1B/1D) receptor agonist properties may result from inhibition of nociceptive transmission in the spinal nucleus of the trigeminal nerve by these drugs. On this basis, we have assessed the potential antinociceptive effects of sumatriptan and zolmitriptan, compared to dihydroergotamine (DHE), in a rat model of trigeminal neuropathic pain. 2. Chronic constriction injury was produced by two loose ligatures of the infraorbital nerve on the right side. Responsiveness to von Frey filament stimulation of the vibrissal pad was used to evaluate allodynia. 3. Two weeks after ligatures, rats with a chronic constriction of the right infraorbital nerve displayed bilateral mechanical hyper-responsiveness to von Frey filament stimulation of the vibrissal pad with a mean threshold of 0.38 +- 0.04g on the injured side and of 0.43 +- 0.04g on the contralateral (left) side (versus ≥ 12.5g on both sides in the same rats prior to nerve constriction injury). 4. Sumatriptan at a clinically relevant dose (100 μg kg~(-1), s.c.) led to a significant reduction of the mechanical allodynia-like behaviour on both the injured and the contralateral sides (peak-effects 6.3 +- 1.1g and 4.4 +- 0.7g, respectively). A more pronounced effect was obtained with zolmitriptan (100 μg kg~(-1), s.c.) (peak-effects: 7.4 +- 0.9g and 3.2 +- 1.3g) whereas DHE (50-100 μg kg~(-1), i.v.) was less active (peak-effect ～1.5g). 5. Subcutaneous pretreatment with the 5-HT_(1B/1D) receptor antagonist, GR 127935 (3 mg kg~(-1)), prevented the anti-allodynia-like effects of triptans and DHE. Pretreatment with the 5-HT_(1A) receptor antagonist, WAY 100635 (2mg kg~(-1), s.c.), did not alter the effect of triptans but significantly enhanced that of DHE (peak effect 4.3 +- 0.5g). 6. In a rat model of peripheral neuropathic pain, which consisted of a unilateral loose constriction of the sciatic nerve, neither sumatriptan (50-300 μg kg~(-1)) nor zolmitriptan (50-300 μg kg~(-1)) modified the thresholds for paw withdrawal and vocalization in response to noxious mechanical stimulation. 7. These results support the rationale for exploring the clinical efficacy of brain penetrant 5-HT_(1B/1D) receptor agonists as analgesics to reduce certain types of trigeminal neuropathic pain in humans.