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 e ect 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 e ects 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 ®lament 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 ®lament 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 512.5 g on both sides in the same rats prior to nerve constriction injury). 4 Sumatriptan at a clinically relevant dose (100 mg kg 71 , s.c.) led to a signi®cant reduction of the mechanical allodynia-like behaviour on both the injured and the contralateral sides (peak-e ects 6.3+1.1 g and 4.4+0.7 g, respectively). A more pronounced e ect was obtained with zolmitriptan (100 mg kg 71 , s.c.) (peak-e ects: 7.4+0.9 g and 3.2+1.3 g) whereas DHE (50 ± 100 mg kg 71 , i.v.) was less active (peak-e ect *1.5 g). 5 Subcutaneous pretreatment with the 5-HT 1B/1D receptor antagonist, GR 127935 (3 mg kg 71 ), prevented the anti-allodynia-like e ects of triptans and DHE. Pretreatment with the 5-HT 1A receptor antagonist, WAY 100635 (2 mg kg 71 , s.c.), did not alter the e ect of triptans but signi®cantly enhanced that of DHE (peak e ect 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 mg kg 71 ) nor zolmitriptan (50 ± 300 mg kg 71 ) modi®ed the thresholds for paw withdrawal and vocalization in response to noxious mechanical stimulation. 7 These results support the rationale for exploring the clinical e cacy of brain penetrant 5-HT 1B/1D receptor agonists as analgesics to reduce certain types of trigeminal neuropathic pain in humans.

Where do triptans act in the treatment of migraine?

“…In another study, sumatriptan reduced pain-related behaviors following acute intracarotid injection of bradykinin in rats (Ottani et al, 2004) but the study did not include a comparable model of somatic pain. Finally, a detailed study comparing neuropathic models of trigeminal and sciatic pain did detect a selective antinociceptive effect for trigeminal pain with both sumatriptan and zolmitriptan (Kayser et al, 2002). In contrast, evidence for the nonselective activity of triptans was reported in an inflammatory model of pain, where sumatriptan dose-dependently reduced behavioral signs of hyperalgesia after carageenan injection of the mouse hindpaw (Bingham et al, 2001).…”

Tissue Injury Regulates Serotonin 1D Receptor Expression: Implications for the Control of Migraine and Inflammatory Pain

“…Somewhat paradoxically, Kayser et al (2002) reported an analgesic effect of triptans after chronic constriction injury of the infraorbital nerve, but saw no analgesic effect after constriction injury of the sciatic nerve. Because there are certainly differences in the central consequences of complete transection versus chronic constriction injury, it will be of great interest to determine whether dorsal horn 5-HT 1D -IR is regulated differently in the latter model of neuropathic pain.…”

Differential Implication of Proinflammatory Cytokine Interleukin-6 in the Development of Cephalic versus Extracephalic Neuropathic Pain in Rats

“…Numerous studies have revealed differences between the pain syndrome caused by injury to the trigeminal nerve and those occurring after lesion of other peripheral nerves (Tal and Devor, 1992;Benoliel et al, 2001;Kayser et al, 2002), suggesting the existence of distinct pathophysiological mechanisms in the cephalic versus extracephalic territories (Bennett, 2004). Precise pathophysiological mechanisms implicated in the development of neuropathic pain states are still unclear, but numerous data have recently suggested a major role for activated glial cells via the production of cytokines (Watkins et al, 2001).…”