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

Abstract

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+/-0.04 g on the injured side and of 0.43+/-0.04 g on the contralateral (left) side (versus > or =12.5 g on both sides in the same rats prior to nerve constriction injury). 4. Sumatriptan at a clinically relevant dose (100 microg 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+/-1.1 g and 4.4+/-0.7 g, respectively). A more pronounced effect was obtained with zolmitriptan (100 microg kg(-1), s.c.) (peak-effects: 7.4+/-0.9 g and 3.2+/-1.3 g) whereas DHE (50-100 microg kg(-1), i.v.) was less active (peak-effect approximately 1.5 g). 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 (2 mg kg(-1), s.c.), did not alter the effect of triptans but significantly enhanced that of DHE (peak effect 4.3+/-0.5 g). 6. In a rat model of peripheral neuropathic pain, which consisted of a unilateral loose constriction of the sciatic nerve, neither sumatriptan (50-300 microg kg(-1)) nor zolmitriptan (50-300 microg 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.

Figure 1

Mechanical response thresholds before (‘Pre ligature') and 2 weeks after (‘Post ligature') ligature of (A) the right infraorbital nerve or (B) the right sciatic nerve. Response thresholds were determined in the territories ipsilateral and contralateral to the ligature. Data (means±s.e.m., A: n=138, B: n=18) are expressed as grams (g). ***P<0.001 versus pre ligature value.

Figure 2

Time-course curves of the effects of various doses of dihydroergotamine (DHE) or saline on the mechanical response thresholds in the infraorbital nerve territory ipsilateral and contralateral to the ligature. Data (means±s.e.m., n=6) are expressed as grams (g). *P<0.05 versus saline.

Figure 3

Time-course curves of the effects of various doses of sumatriptan or saline on the mechanical response thresholds in the infraorbital nerve territory ipsilateral and contralateral to the ligature. Data (means±s.e.m., n=6) are expressed as grams (g). *P<0.05, **P<0.01, ***P<0.001 versus saline.

Figure 4

Time-course curves of the effects of various doses of zolmitriptan or saline on the mechanical response thresholds in the infraorbital nerve territory ipsilateral and contralateral to the ligature. Data (means±s.e.m., n=6) are expressed as grams (g). *P<0.05, **P<0.01, ***P<0.001 versus saline.

Figure 5

Areas under the curves (AUC, g×min, means±s.e.m.) of the respective time-course curves in Figures 2,3,4 (open bars) and effect of pretreatment with GR 127935 (3 mg kg⁻¹, s.c. 20 min before, hatched bars) on mechanical response thresholds in the infraorbital nerve territory ipsilateral and contralateral to the ligature after administration of dihydroergotamine (DHE, 50 μg kg⁻¹, i.v.), sumatriptan (Suma, 100 μg kg⁻¹, s.c.) or zolmitriptan (Zolmi, 100 μg kg⁻¹, s.c.). **P<0.01, ***P<0.001 versus saline, ^•P<0.05, ^•••P<0.001 versus treatment with DHE, sumatriptan or zolmitriptan alone, n=6 in each group.

Figure 6

Effect of pretreatment with WAY 100635 (2 mg kg⁻¹, s.c., 20 min before) on dihydroergotamine (DHE, 50 μg kg⁻¹, i.v.)-induced changes in the mechanical response thresholds in the infraorbital nerve territory ipsilateral or contralateral to the ligature. Results are expressed as (A) the time-course curves of the mean±s.e.m., in grams, of the response thresholds and (B) the mean±s.e.m. of areas under the time-course curves (AUC) calculated by the trapezoidal rule (see Methods). ^•P<0.05, ^•••P<0.01 versus saline; *P<0.05 versus DHE (50 μg kg⁻¹, i.v.) alone, n=6 in each group.