Lack of Antinociceptive Activity of Sumatriptan in Rodents

Skingle, M.; Birch, P.J.; Leighton, G.E.; Humphrey, P. P. A.

doi:10.1046/j.1468-2982.1990.1005207.x

Cited by 49 publications

(23 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, although triptans have no effect on acute mechanical or thermal nociceptive thresholds (Skingle et al, 1990), Bingham et al (2001) and our own preliminary studies reveal antinociceptive effects of sumatriptan after inflammatory injury, through an action predominantly at the spinal cord dorsal horn (Nikai et al, 2005).…”

Section: Are Triptans General Analgesics?mentioning

confidence: 89%

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

Ahn

Basbaum²

2006

J. Neurosci.

View full text Add to dashboard Cite

The anti-migraine action of "triptan" drugs involves the activation of serotonin subtype 1D (5-HT 1D ) receptors expressed on "painresponsive" trigeminal primary afferents. In the central terminals of these nociceptors, the receptor is concentrated on peptidergic dense core vesicles (DCVs) and is notably absent from the plasma membrane. Based on this arrangement, we hypothesized that in the resting state the receptor is not available for binding by a triptan, but that noxious stimulation of these afferents could trigger vesicular release of DCVs, thus externalizing the receptor. Here we report that within 5 min of an acute mechanical stimulus to the hindpaw of the rat, there is a significant increase of 5-HT 1D -immunoreactivity (IR) in the ipsilateral dorsal horn of the spinal cord. We suggest that these rapid immunohistochemical changes reflect redistribution of sequestered receptor to the plasma membrane, where it is more readily detected. We also observed divergent changes in 5-HT 1D -IR in inflammatory and nerve-injury models of persistent pain, occurring at least in part through the regulation of 5-HT 1D -receptor gene expression. Finally, we found that 5-HT 1D -IR is unchanged in the spinal cord dorsal horn of mice with a deletion of the gene encoding the neuropeptide substance P. This result differs from that reported for the Ѩ-opioid receptor, which is also sorted to DCVs, but is greatly reduced in preprotachykinin mutant mice. We suggest that a "pain"-triggered regulation of 5-HT 1D -receptor expression underlies the effectiveness of triptans for the treatment of migraine. Moreover, the widespread expression of 5-HT 1D receptor in somatic nociceptive afferents suggests that triptans could, in certain circumstances, treat pain in nontrigeminal regions of the body.

show abstract

Section: Are Triptans General Analgesics?mentioning

confidence: 89%

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

Ahn

Basbaum²

2006

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Behavioral models of triptan action also argue selectivity for cranial pain, with some exceptions. For example, a preliminary study of acute somatic thermal or mechanical pain in rodents did not detect an antinociceptive effect of sumatriptan (Skingle et al, 1990). 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.…”

Section: Are Triptans Migraine-selective?mentioning

confidence: 99%

Where do triptans act in the treatment of migraine?

Ahn

Basbaum

2005

Pain

117

View full text Add to dashboard Cite

Migraine headache is a pervasive but poorly understood primary pain disorder. Sumatriptan and the 'triptan' class of serotonin receptor subtype-selective drugs have well-established efficacy in treating the pain of migraine. Although sumatriptan was originally selected to target vasoactive properties thought to be fundamental to the etiology of migraine, other studies point to an action of triptans at several levels of the nervous system. To this day, however, it is not clear whether the antimigraine activity of the triptans involves an action only in the periphery or in the CNS as well. Because sumatriptan is hydrophilic, it penetrates the blood-brain barrier poorly, suggesting a peripheral site of action. On the other hand, it has been proposed that the barrier is compromised in migraineurs, so a CNS site of action has not been ruled out. Finally, the basis for the apparent selectivity of triptans in the treatment of migraine pain but not other kinds of somatic pain is still not understood. Determining that mechanism of triptan action will likely provide important new insights into the unique and essential features of migraine. Graham and Wolff (1938) first proposed that the pain of migraine results from abnormal cranial vascular distention. They were influenced by (1) the association between migraine relieving properties of ergotamine tartrate infusion and arterial vasoconstriction and (2) the finding that compression of the common carotid artery or superficial temporal artery reduces pain in many migraine attacks. Although the relationship between vascular changes and migraine was still uncertain, the vasoactive, serotonergic properties of ergotamine on isolated artery and vein preparations led to the development of sumatriptan, a serotonergic agonist with selective activity on 5-HT 1B , 5-HT 1D , and 5-HT 1F receptors. The vasoconstrictive properties of triptans are mediated by an action on 5-HT 1B in arterial smooth muscle. On the other hand, although sumatriptan-mediated vasoconstriction can dose-dependently increase blood flow velocity in middle cerebral vessels, because these vascular changes are not temporally related to the resolution of the migraine attack (Limmroth et al., 1996), it is still unclear whether triptan activation of vascular 5-HT 1B receptors is necessary for the treatment of migraine. Peripheral mechanismsThe triptans are also thought to inhibit the abnormal activation of peripheral nociceptors. In an experimental model of migraine, called sterile neurogenic inflammation, an abnormal activation of nociceptors in the dura mater triggers vascular changes, including plasma protein *

show abstract

“…The mean serum levels of sumatriptan measured 2 h after dosing after 4 weeks of treatment at 360 mg kg-I day 1 was 8-9 mcg mL-1 whereas by 13 weeks it was 23-26 mcg mL-1. Reduction of the top dose level to 160 mg kg-1 was associated with 2 h levels of [11][12][13][14][15][16][17][18][19][20][21][22] mcg mL-1 in Week 22. Despite the reduction in dose level, serum concentrations were dose related, ranging from approximately twice the peak concentration of the drug after the recommended human subcutaneous dose of 6 mg at the low dose to more than 100 times this concentration at the high dose.…”

Section: Necropsy Findingsmentioning

confidence: 99%

“…Animal data indicate that sumatriptan Table 1 The toxicological evaluation of sumatriptan -studies performed has no analgesic activity. 12 To support world-wide marketing applications a series of toxicity studies was performed via the clinical routes (oral and subcutaneous). Intravenous studies were also performed so as to allow initial human volunteer studies to be conducted by this route.…”

Section: Introductionmentioning

confidence: 99%

The preclinical toxicological evaluation of sumatriptan

et al. 1995

View full text Add to dashboard Cite

1 Sumatriptan is a potent and selective 5-HT1 receptor agonist marketed for the treatment of migraine by both oral and subcutaneous routes. An extensive toxicologi cal programme employing high doses of sumatriptan was carried out in a range of animal species. The stud ies evaluated both the local and systemic tolerance to single and repeated dosing, effects on all stages of repro duction, as well as the genotoxic and oncogenic poten tial of sumatriptan. 2 The administration of relatively high single and repeat ed doses of sumatriptan was well tolerated by both rodents and dogs by the oral, subcutaneous and intra venous routes. Behavioural effects, suggestive of involvement of the central nervous system, were the most obvious result of such doses and were generally more pronounced in dogs than rodents. The reason for this may be related to the higher plasma concentrations of the drug achievable in dogs. Additional observations restricted to dogs, were transient, and included tachy cardia, facial oedema and breaks in the continuity of secretion films on the corneal surface. A tendency for an increase in weight gain was seen for rats, while a slight decrease was usually seen for dogs. The only pathologi cal changes related to treatment with high concentra tions of sumatriptan consisted of local reactions at the site of subcutaneous administration. 3 Sumatriptan is an indole; the structures of this chemical class show varying propensities for nitrosation. However, appropriate testing with sumatriptan failed to identify any mutagenic nitroso compounds. 4 Sumatriptan was neither genotoxic nor oncogenic. 5 Reproductive studies demonstrated that sumatriptan was not teratogenic and had no effect on peri- and post natal development. Some embryotoxicity was observed, but only at maternally toxic doses. A slight decrease in the success of insemination was also noted at high oral doses in rats. 6 Results of the toxicological programme performed in support of migraine therapy with sumatriptan provide good assurance of safety for subcutaneous and oral use.

show abstract

Lack of Antinociceptive Activity of Sumatriptan in Rodents

Cited by 49 publications

References 19 publications

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

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

Where do triptans act in the treatment of migraine?

The preclinical toxicological evaluation of sumatriptan

Contact Info

Product

Resources

About