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Profound reduction of somatic and visceral pain in mice by intrathecal administration of the anti-migraine drug, sumatriptan.

ABSTRACT: Sumatriptan and the other triptan drugs target the serotonin receptor subtypes1B, 1D, and 1F (5-HT(1B/D/F)), and are prescribed widely in the treatment of migraine. An anti-migraine action of triptans has been postulated at multiple targets, within the brain and at both the central and peripheral terminals of trigeminal "pain-sensory" fibers. However, as triptan receptors are also located on "pain-sensory" afferents throughout the body, it is surprising that triptans only reduce migraine pain in humans, and experimental cranial pain in animals. Here we tested the hypothesis that sumatriptan can indeed reduce non-cranial, somatic and visceral pain in behavioral models in mice. Because sumatriptan must cross the blood brain barrier to reach somatic afferent terminals in the spinal cord, we compared systemic to direct spinal (intrathecal) sumatriptan. Acute nociceptive thresholds were not altered by sumatriptan pre-treatment, regardless of route. However, in behavioral models of persistent inflammatory pain, we found a profound anti-hyperalgesic action of intrathecal, but not systemic, sumatriptan. By contrast, sumatriptan was completely ineffective in an experimental model of neuropathic pain. The pronounced activity of intrathecal sumatriptan against inflammatory pain in mice raises the possibility that there is a wider spectrum of therapeutic indications for triptans beyond headache.

SUBMITTER: Nikai T

PROVIDER: S-EPMC2869302 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Profound reduction of somatic and visceral pain in mice by intrathecal administration of the anti-migraine drug, sumatriptan.

Nikai Tetsuro T Basbaum Allan I AI Ahn Andrew H AH

Pain 20080823 3

Sumatriptan and the other triptan drugs target the serotonin receptor subtypes1B, 1D, and 1F (5-HT(1B/D/F)), and are prescribed widely in the treatment of migraine. An anti-migraine action of triptans has been postulated at multiple targets, within the brain and at both the central and peripheral terminals of trigeminal "pain-sensory" fibers. However, as triptan receptors are also located on "pain-sensory" afferents throughout the body, it is surprising that triptans only reduce migraine pain in ...[more]

PMID: 18723285

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Project description:ImportanceTriptans, the most efficient acute treatment for migraine attacks, are 5-HT1B/1D receptor agonists, but their precise mechanism of action is not completely understood. The extent to which triptans enter the central nervous system and bind to 5-HT1B receptors in the brain is unknown.ObjectivesTo determine the occupancy of sumatriptan to central 5-HT1B receptors, and to investigate changes in brain serotonin levels during migraine attacks.Design, setting, and participantsThis study of 8 patients in Denmark used a within-participant design and was conducted from April 20, 2015, to December 5, 2016. Participants were otherwise healthy patients with untreated episodic migraine without aura, aged between 18 and 65 years, and recruited from the general community. Data analysis was performed from January 2017 to April 2018.InterventionsAll participants underwent positron emission tomographic scans after injection of [11C]AZ10419369, a specific 5-HT1B receptor radiotracer. All participants were scanned 3 times: (1) during an experimentally induced migraine attack, (2) after a subcutaneous injection of 6-mg subcutaneous sumatriptan, and (3) on a migraine attack-free day. Scans 1 and 2 were conducted on the same study day. Each scan lasted for 90 minutes.Main outcome and measureThe primary outcome was the nondisplaceable binding potential of [11C]AZ10419369 across 7 brain regions involved in pain modulation. The binding potential reflects receptor density, and changes in binding potential reflects displacement of the radiotracer. The occupancy of sumatriptan was estimated from the 2 scans before and after sumatriptan administration.ResultsEight patients with migraine were included in the study; of these participants, 7 (87%) were women. The mean (SD) age of participants on study day 1 was 29.5 (9.2) years and on study day 2 was 30.0 (8.9) years. Sumatriptan was associated with statistically significantly reduced 5-HT1B receptor binding across pain-modulating regions (mean [SD] binding potential, 1.20 [0.20] vs 1.02 [0.22]; P = .001), corresponding to a mean (SD) drug occupancy rate of 16.0% (5.3%). Furthermore, during migraine attacks, as compared with outside of attacks, 5-HT1B receptor binding was statistically significantly associated with reduced in pain-modulating regions (mean [SD] binding potential, 1.36 [0.22] vs 1.20 [0.20]; P = .02).Conclusions and relevanceTreatment with sumatriptan during migraine attacks appeared to be associated with a decrease in 5-HT1B receptor binding, a finding that is most likely associated with the binding of sumatriptan to central 5-HT1B receptors, but the contribution of ongoing cerebral serotonin release to the lower binding cannot be excluded; the migraine attack-associated decrease in binding could indicate that migraine attacks are associated with increases in endogenous serotonin.

Project description:ObjectiveThis study aimed to investigate the efficacy of intrathecal morphine in the long term by hypothesising that a reduction of the intrathecal opioid dose following long-term administration would increase the level of pain intensity.DesignRandomised, double-blind, controlled, parallel group trial.SettingDepartment of Pain Management, Russells Hall Hospital, Dudley, UK.Participants24 patients with non-cancer pain implanted with morphine reservoirs were assessed for eligibility.InterventionsParticipants were randomly allocated to one of two parallel groups in which one of the groups had no change in morphine dose and the other group had a small reduction (20%) in dosage every week during a 10-week follow-up.OutcomePrimary outcomes were visual analogue scale (VAS) pain score change and withdrawal from the study due to lack of efficacy.Results9 of the patients assessed for eligibility declined to participate in the study. 15 patients were randomised to control (n=5) or intervention (n=10) and included in an intention-to-treat analysis. Owing to worsening of pain, seven patients withdrew from the study prematurely. None knew prior to withdrawal which arm of the study they were in, but all turned out to be in the dose-reduction arm. The calculation of dropout rates between groups indicated a significant statistical difference (p=0.026) and recruitment was ceased. The VAS change between baseline and the last observation was smaller in the control group (median, Mdn=11) than in the intervention group (Mdn=30.5), although not statistically significant, Z=-1.839, p=0.070; r=-0.47. Within groups, VAS was significantly lower at baseline (Mdn=49.5) than at the last observation (Mdn=77.5) for the reduction group, Z=-2.805, p=0.002; r=-0.627 but not for the control group (p=0.188).ConclusionsThis double-blind randomised controlled trial of chronic intrathecal morphine administration suggests the effectiveness of this therapy for the management of chronic non-cancer pain. However, owing to the small number of patients completing the study (n=8), further studies are warranted.Trial registrationInternational Standard Randomised Controlled Trials Centre (ISRCTN 33733462).

Project description:BACKGROUND:The primary goal of this study was to determine whether administration of intrathecal morphine reduces postoperative pain. The secondary goal was to determine the effect of intrathecal morphine upon circulating levels of the weakly analgesic endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the related lipids palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). METHODS:Forty two total knee arthroplasty (TKA) patients were enrolled in a prospective, double-blinded, randomized study. The intervention consisted of intrathecal morphine (200 ?g) or placebo administered at the time of the spinal anesthesia. Postoperative pain was measured during the first 4 h after surgery while serum levels of AEA, 2-AG, PEA, OEA, and cortisol were measured at baseline and 4 h after surgery. RESULTS:Administration of intrathecal morphine reduced postoperative pain 4 h after TKA surgery compared to placebo (p?=?0.005) and reduced postoperative systemic opioid consumption (p?=?0.001). At baseline, intrathecal morphine led to a significant reduction in AEA, 2-AG, and OEA levels but did not affect PEA or cortisol levels. In patients administered intrathecal placebo, 2-AG levels were elevated 4 h after surgery; whereas patients receiving intrathecal morphine showed reductions in AEA, PEA, and OEA when compared to placebo. At 4 h after TKA surgery cortisol levels were significantly elevated in the placebo group and reduced in those receiving morphine. CONCLUSIONS:These results indicate that intrathecal morphine reduces postoperative pain in TKA patients. Furthermore, activation of central opioid receptors negatively modulates the endocannabinoid tone, suggesting that potent analgesics may reduce the stimulus for production of peripheral endocannabinoids. This study is the first to document the existence of rapid communication between the central opioid and peripheral endocannabinoid systems in humans. TRIAL REGISTRATION:This trial was registered retrospectively. TRIAL REGISTRY:NCT02620631 . Study to Examine Pain Relief With Supplemental Intrathecal Morphine in TKA Patients, NCT02620631 , 12/03/2015.

Dataset Information

Profound reduction of somatic and visceral pain in mice by intrathecal administration of the anti-migraine drug, sumatriptan.

Publications

Profound reduction of somatic and visceral pain in mice by intrathecal administration of the anti-migraine drug, sumatriptan.

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