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Abstract

Background

Loss of conditioned pain modulation/diffuse noxious inhibitory controls has been demonstrated in patients with migraine and medication overuse headache. We hypothesized that exposure to acute migraine medications may lead to dysregulation of central pain modulatory circuits that could be revealed by evaluating diffuse noxious inhibitory controls and that prior noxious stimulus is required for a loss of the diffuse noxious inhibitory control response in rats exposed to these medications.

Methods

Rats were “primed” by continuous infusion of morphine or one of two doses of sumatriptan. Diffuse noxious inhibitory control was evaluated at the end of drug-priming (day 7) and again after sensory thresholds returned to baseline (day 21). The Randall-Selitto hindpaw pressure test was used as the test stimulus and forepaw capsaicin injection served as the conditioning stimulus.

Results

Morphine-primed rats showed opioid-induced hyperalgesia accompanied by a loss of diffuse noxious inhibitory controls on day 7. Sumatriptan-primed rats did not develop hyperalgesia or loss of diffuse noxious inhibitory controls on day 7. Morphine-primed and high-dose sumatriptan-primed rats only had a loss of diffuse noxious inhibitory control on day 21 if they received a capsaicin injection on day 7.

Conclusions

Prolonged exposure to migraine treatments followed by an acute nociceptive stimulation caused long-lasting alterations in descending pain modulation, shown by a loss of diffuse noxious inhibitory controls. Morphine was more detrimental than sumatriptan, consistent with clinical observations of higher medication overuse headache risk with opioids. These data suggest a mechanism of medication overuse headache by which migraine medications combined with repeated episodes of pain may amplify the consequences of nociceptor activation and increase the probability of future migraine attacks as well as risk of medication overuse headache.

Keywords

Conditioned pain modulation diffuse noxious inhibitory controls opioid induced hyperalgesia hyperalgesic priming sumatriptan morphine

Introduction

Chronic pain conditions that consist of intermittent pain episodes and that lack a distinguishable injury or that are not associated with an acute noxious stimulus are difficult to study in rodent models since (a) such conditions are not known to occur naturally in these species; and (b) unlike acute nociceptive or neuropathic pain, these functional pain syndromes (FPS) lack a clear etiology, compounding the difficulty of establishing relevant models (1,2). We have previously used a “two-hit” model of hyperalgesic priming as an approach to investigate FPS including medication overuse headache (MOH) (3 –7). This approach involves administration of acute migraine medications that serve as the first “hit”, eliciting a state of “latent sensitization” in which normally innocuous stimuli; that is, the second “hit”, produce allodynia (1,2,8,9). This “two-hit” hyperalgesic priming method is useful for the study of FPS because it produces prolonged alterations in responses to acute nociceptive stimuli even in the absence of evidence of ongoing pain. This replicates, in part, the phenotype of intermittent pain attacks brought on by stimuli that would normally be considered non-noxious or would be expected to elicit a much smaller nociceptive response (10).

Diffuse noxious inhibitory controls (DNIC) is a “pain inhibits pain” phenomenon that is a dynamic assessment of the strength of net descending pain inhibition (11 –14). In humans, the DNIC response is referred to as conditioned pain modulation (CPM) and is diminished in patients with numerous functional pain disorders, including MOH and opioid-induced hyperalgesia (OIH), suggesting that it may be a relevant output measure for exploring the neural mechanisms that underlie FPS (15 –17). Here, we studied the effects of sumatriptan and morphine priming on DNIC after either single or repeated exposures to capsaicin, an acute noxious stimulus.

Methods

Animals: Male Sprague-Dawley rats (175–200 g, Envigo, Indianapolis, Indiana, USA) were used in this study. Experiments were carried out in accordance with policies set forth by the NIH guidelines for use of laboratory animals and approval from the IACUC at the University of Arizona. Rats were kept in a climate controlled room on a 12 hour light and 12 hour dark cycle with ad libitum access to food and water. We adhered to the ARRIVE guidelines wherever possible. Animals were randomly assigned to experimental groups and the experimenter was blinded to the treatments.

Drug priming: Osmotic minipumps (Model 2001, Alzet, Cupertino, California, USA) (1 μl/hr) to deliver vehicle (0.9% saline, VetOne, Boise, Idaho, USA), sumatriptan succinate (0.6 mg/kg/day or 3 mg/kg/day, Tocris), or morphine sulfate (7.68 mg/kg/day, NIH-NIDA drug supply) for 7 days were implanted subcutaneously. These doses were chosen on the basis of previously published or pilot studies in our laboratory (3 –5,18). Drug-priming was used as the “first hit”.

Conditioning stimulus: An intradermal capsaicin (Sigma-Aldrich, St Louis, Missouri, USA) injection was used as the conditioning stimulus to induce DNIC. Capsaicin was prepared as previously described (3,19). Briefly, capsaicin was mixed to an initial concentration of 50 µg/μl in a solution containing 1:1 ethanol:tween 80 and then diluted to the final concentration of 2.5 µg/μl using 0.9% saline. Rats were briefly anesthetized with isoflurane and injected with 50 μl (125 µg capsaicin) of capsaicin solution into the left forepaw. Rats received either a capsaicin or vehicle injection into the left forepaw on day 7. On day 21, all rats received capsaicin. D7 capsaicin was used as the “second hit” in this model of hyperalgesic priming.

Test stimulus: The Randall–Selitto paw pressure test (Ugo Basile, Varese, Italy) was used to measure changes in static nociceptive thresholds during priming and as the test stimulus to quantify the DNIC response. The pressure at which the rat vocalized or withdrew its hindpaw was recorded as the paw withdrawal threshold (PWT). PWT was measured three times for each hindpaw at each time point and averaged prior to data analysis. Since left and right hindpaw measurements were not significantly different from each other, the withdrawal thresholds for both hindpaws were averaged together for data analysis.

Statistics: Analysis of mechanical hyperalgesia on day 7 and day 21 was performed using a two-way analysis of variance (ANOVA) followed by Dunnett’s test for multiple comparisons. PWTs of rats within the same drug-priming group that received day 7 capsaicin or day 7 vehicle forepaw injection did not differ significantly from each other at day 0, day 7, or day 21, so these groups were combined for the assessment of mechanical hyperalgesia. DNIC timecourses were analyzed by two-way ANOVA followed by Sidak’s test for multiple comparisons. Data shown as percent maximal response were calculated by subtracting the baseline value from the test point value and dividing by the cutoff value (500 g) minus the baseline value. Statistics were calculated using GraphPad Prism 7 software.

Results

Morphine, but not sumatriptan, produces mechanical hyperalgesia

Morphine-treated rats had significant mechanical hyperalgesia; that is, opioid-induced hyperalgesia (OIH), on day 7, the last day of administration (p < 0.0001, F_(6,154) = 5.121, Figure 1). Hyperalgesia resolved by day 21, two weeks after the end of drug treatment (Figure 1). Neither dose of sumatriptan produced significant mechanical hyperalgesia (Figure 1).

Figure 1.

Morphine but not sumatriptan priming causes hyperalgesia that resolves by day 21 after the start of treatment. Morphine priming causes hyperalgesia on day 7, the last day of morphine treatment. This hyperalgesia resolves by day 21. Neither dose of sumatriptan produced significant hyperalgesia. Day 0: baseline prior to start of drug or saline priming; day 7: last day of drug or saline priming; day 21: 14 days after end of drug or saline priming.

Loss of DNIC occurs both on day 7 during OIH, as well as following resolution of hyperalgesia at day 21

The timeline used for this experiment is shown above the graphs. Morphine priming produced a significant loss of DNIC on day 7, a timepoint at which morphine-primed rats have OIH (p < 0.0001, F_(4,68) = 7.371, Figure 2(a)). When DNIC was tested again on day 21, these morphine-primed rats still showed a loss of DNIC compared to saline-primed controls (p < 0.0001, F_(4,68) = 14.72, Figure 2(b)) despite no observable differences in baseline paw withdrawal thresholds (i.e. no OIH) at this timepoint.

Figure 2.

Morphine priming causes a loss of DNIC on day 7 and morphine-primed rats that received capsaicin, but not vehicle, on day 7 also have a loss of DNIC on day 21. The experimental timelines are shown above the graphs for clarity. Rats that were primed with morphine have a significant loss of DNIC on day 7, the last day of morphine treatment and a timepoint when rats are exhibiting OIH (a). Morphine primed rats that received an injection of capsaicin on day 7 also have a loss of DNIC on day 21 (b). A separate group of rats were given a forepaw injection of vehicle instead of capsaicin on day 7 and exhibited no significant change in paw withdrawal threshold from day 7 baseline after vehicle injection (c). Morphine-primed rats did not have a loss of DNIC on day 21 if they received forepaw vehicle instead of capsaicin on day 7 (d).

Morphine priming alone is not sufficient to cause a loss of DNIC on day 21 without the prior capsaicin “second hit” on day 7

A different group of rats received morphine priming followed by a forepaw injection of vehicle, instead of capsaicin, on day 7. The timeline used for this experiment is shown above Figures 2(c) and (d). The rats that received a forepaw vehicle injection on day 7 did not exhibit any changes in PWT from the day 7 baseline during the 90 minutes of testing after vehicle injection, confirming that saline injection did not produce hyperalgesia (Figure 2(c)). When DNIC was tested on day 21, the morphine-primed rats did not exhibit a loss of DNIC compared to saline-primed controls (Figure 2(d)).

High, but not low, dose sumatriptan priming followed by exposure to a capsaicin second hit produces a loss of DNIC on day 21

The experimental timeline for this experiment is shown above Figures 3(a) and (b). Sumatriptan-primed rats did not exhibit a loss of DNIC compared to saline-primed controls on day 7, the last day of drug priming (Figure 3(a)). However, when DNIC was tested again on day 21 in the same rats, there was a significant loss of DNIC in rats that had received the 3 mg/kg/day dose of sumatriptan (p < 0.0001, F_(8,128) = 5.1, Figure 3(b)) while rats receiving the 0.6 mg/kg/day dose of sumatriptan did not have a significant loss of DNIC.

Figure 3.

High-, but not low-dose sumatriptan priming followed by capsaicin exposure produces a loss of DNIC on day 21. The experimental timeline for each experiment is shown above the graphs. Neither dose of sumatriptan was sufficient to cause a loss of DNIC on day 7, the last day of drug-priming (a). However, rats that received capsaicin injection on day 7 and that were primed with the higher dose of sumatriptan had a loss of DNIC on day 21 (b). A separate cohort of rats was given a forepaw injection of vehicle instead of capsaicin on day 7 and exhibited no significant change in paw withdrawal threshold from day 7 baseline after vehicle injection (c). Neither dose of sumatriptan produced a significant loss of DNIC on day 21 in rats that had vehicle injection on day 7 (d).

Sumatripan priming alone is not sufficient to cause loss of DNIC on day 21

A separate cohort of rats that received sumatriptan priming were given a forepaw injection of vehicle instead of capsaicin on day 7. The timeline for this experiment is shown above Figures 3(c) and (d). Rats that received a forepaw injection of vehicle on day 7 had no change in paw withdrawal threshold in the 90 minutes following vehicle injection (Figure 3(c)). These rats were then injected with capsaicin on day 21 to test the DNIC response. Neither dose of sumatriptan produced a loss of DNIC on day 21 under these conditons (Figure 3(d)).

Discussion

Functional pain syndromes (FPS), including migraine and medication overuse headache (MOH), are characterized by pain without an obvious inciting event or tissue injury (20,21). Multiple classes of drugs including opioids, triptans, and other acute headache medications can induce MOH (22). However, the susceptibility of patients to develop MOH varies across drug classes, with overuse of opioids being associated with a greater propensity to induce this effect than with triptans; opioid use on 8 days per month or triptan use on 10 days per month are reported to increase the likelihood of transforming episodic migraine into chronic migraine (22 –24). As MOH can result from drugs with very different mechanisms of action, and often has a phenotype of frequent migraine episodes, it seems reasonable to suggest that the overuse of these medications may ultimately converge on common mechanisms that promote migraine attacks (25). One possible mechanism that may be common across classes of drugs is dysregulation of descending pain modulatory circuits to result in a net descending facilitation. The present study adds to our previous observations suggesting that multiple classes of drugs can act as a priming stimulus – a “first hit” that promotes central sensitization and amplifies responses to subsequent provocative stimuli; that is, the “second hit”, by enhancement of net descending facilitation in central pain modulatory pathways (3 –7). The ability of an acute noxious stimulus into the forepaw (i.e. day 7 capsaicin) to produce a latent loss of DNIC in the hindpaw of sumatriptan- or morphine-primed rats strongly suggests that central sensitization is occurring in this model.

We treated rats with morphine or with one of two doses of sumatriptan to induce a sensitized state without injury, similar to that seen in FPS. Opioids, but not triptans, are known to produce a long-lasting neural amplification of noxious stimuli termed opioid-induced hyperalgesia (OIH) in humans and in animals (26 –30). The 7 day administration protocol used here showed significant hyperalgesia induced by morphine, but not by either dose of sumatriptan. Morphine-induced hyperalgesia resolved by 14 days after the termination of the 7-day course of morphine treatment. While sumatriptan administration did not significantly alter the paw withdrawal thresholds, in our previous studies the 0.6 mg/kg/day dose of sumatriptan has been shown to cause periorbital and hindpaw allodynia when innocuous von Frey filaments are used (5). It is possible that the changes in hindpaw static sensory thresholds caused by these doses and route of administration of sumatriptan administration are too small to be detectable using the noxious mechanical pressure stimulus. Nevertheless, these previous observations are consistent with the ability of sumatriptan to induce a sensitized state as reflected by generalized cephalic and hindpaw allodynia following exposure to a stress stimulus (4,6,7).

Priming with either a low or high dose of sumatriptan did not induce a loss of the DNIC response when tested on day 7. Addditionally, in rats primed with sumatriptan and receiving forepaw vehicle injection on day 7, no loss of the DNIC response was observed on day 21. However, in rats receiving a high, but not low, dose of sumatriptan and forepaw capsaicin injection on day 7, there was a loss of the DNIC response on day 21. These data suggest that the effects of sumatriptan to promote central dysregulation are dose-dependent and that even a high dose of drug requires an additional priming effect of capsaicin to produce a loss of the DNIC response in this rat model. In contrast, the 0.6 mg/kg/day dose of sumatriptan has previously been shown to decrease the threshold to evoke cortical spreading depression (CSD) on day 21 in rats that have not been exposed to additional priming stimuli (6). Both the loss of DNIC and the increased susceptibility to CSD events are likely mediated by mechanisms that involve central sensitization; however, there may be differences in the degree of sensitization and adaptations within specific circuits that are required to produce these effects. The dose-dependency of the effect of sumatriptan on various measurements of central sensitization, revealed with a short time exposure in rats, might be relevant to the degree of overuse of triptans required to promote MOH in individuals with migraine.

Morphine-primed rats showed a loss of DNIC on day 7, the last day of drug priming, a time when the rats were in a hyperalgesic state. It is possible that the existing hyperalgesia at the time of capsaicin injection was sufficient to precipitate the loss of DNIC. It is important to note that the hypersensitivity detected by static sensory measurements is not required to precipitate a loss of DNIC in this priming model, as both sumatriptan- and morphine-primed rats have a loss of DNIC after the second capsaicin injection on day 21 and neither group has significant hyperalgesia at this timepoint. Rats that received morphine priming followed by forepaw vehicle injection on day 7 did not have a loss of DNIC when this response was engaged on day 21 by capsaicin injection, confirming our previous finding that morphine priming alone was insufficient to cause a loss of DNIC after recovery from OIH (3). These data, along with our previous report of stress-induced loss of DNIC after morphine priming, suggest that a “second hit” by an independent exposure to a noxious or stressful stimulus is required to produce a loss of DNIC after drug priming (3).

Recent studies showed that local administration of 5HT_1B/1D or mu-opioid receptor agonists was sufficient to produce enhanced nociceptive responses to an injection of PGE₂, an inflammatory cytokine, after the hyperalgesia to the priming drug had resolved (8,9,31). These findings demonstrate peripheral mechanisms of nociceptive priming following local injection in the hindpaw while our study used a systemic route of administration for sumatriptan or morphine. The dose and route of administration of the priming drugs used by Levine and colleagues was sufficient to produce hyperalgesia much faster, within hours, than our dosing protocol, which occurred over several days and produced hyperalgesia that persisted for weeks (3,5,8,9,31). Notably, in the case of systemic sumatriptan priming, we did not see significant alterations of the hindpaw withdrawal threshold with the paw pressure test whereas local administration of sumatriptan into the hindpaw caused a significant decrease in hindpaw withdrawal threshold with the same paw pressure test (9). The decrease in paw withdrawal threshold after local administration of sumatriptan may suggest that local hypersensitivity mechanisms in trigeminal nociceptors could also be implicated in MOH. However, the goal of the hyperalgesic priming method used in the present study was to elicit a generalized state of hypersensitivity, occurring body-wide instead of at a single location, which is more typical of the generalized distribution of pain locations seen in FPS patients. Collectively, previous studies and these data reveal that multiple points of sensitization can influence the consequences of a nociceptive stimulus, including primary afferent nociceptors as well as central pain modulatory pathways, revealed here by the evaluation of the DNIC response. Use of these priming models combined with DNIC may be a powerful tool for assessing alterations in central pain modulation pathways that underlie FPS. Future experiments could incorporate the injury-free nature of these paradigms and use DNIC as an output measure to study how manipulations to various brain regions or cell types affect the DNIC response.

Data from the priming model used in these studies, along with our previous reports, demonstrate that acute migraine medications produce prolonged sensitivity to stress and noxious stimuli that may result in intermittent episodes of pain and promote a loss of the DNIC response without injury, traits commonly observed in patients with FPS (3 –7,17,20). Drug-induced priming causes a state of hypersensitivity that appears to resolve after termination of drug treatment, as changes in static sensory thresholds are no longer detected. Nevertheless, challenge with re-exposure to a noxious stimulus or exposure to stress is sufficient to cause a loss of DNIC in these apparently “normal” rats, while exposure to the same noxious or stressful stimuli does not provoke a loss of DNIC in saline-primed control rats. These observations might correlate with the seemingly “normal” state of individuals with migraine in the interictal phase who are nevertheless more susceptible (i.e. sensitized) than those without migraine to develop migraine following a provocative experimental stimulus such as CGRP infusion or NO donor administration and experience increased likelihood of migraine attacks from naturally occurring exogenous environmental stimuli, especially stress, and other disturbances of homeostasis including disruption in sleep and eating patterns (32 –36). Since exposure to acute migraine treatments combined with noxious or stressful stimuli is sufficient to produce a loss of DNIC in rats, it is possible that individuals with migraine exposed to these medications over time become vulnerable to stress and other triggers, causing increasingly frequent attacks, which leads to MOH and a repeating cycle. Additionally, it is possible that migraine patients experience attacks due to poorly understood factors that promote cycling from interictal to ictal states that can occur in the absence of specific triggers and that are promoted by dysregulated descending pain modulatory circuits. Our previous studies suggest that descending pain facilitation, mediated through signaling from the right central nucleus of the amygdala, may contribute to this dysregulation (3,4).

A limitation to this study is that only male rats were used. However, a loss of DNIC has been found in several studies of migraine patients, some that only included female patients and some that included both male and female patients (16,37 –40). Similarly, studies that found no loss of DNIC in migraine patients have been conducted using only female or both male and female patients, suggesting that sex is not the main factor in determining whether or not DNIC is lost in migraine patients (16,41,42). Nevertheless, assessing DNIC in both male and female rodent populations in future experiments may provide further insight into the sexual dimorphism seen in FPS. Another limitation of our study is that the drugs were delivered continuously by the subcutaneous route over a period of days, whereas patients receive these medicines intermittently and frequently by the oral route (43,44). Additionally, we used doses of the drugs that have been shown to have effects in rodents but that cannot be related directly to doses that are used in humans. Despite these limitations, it is clear that both the triptans and opioids produce sensitizing effects in rodents. In this regard, both triptans and opioids have been shown to produce an increase in the number of CGRP positive trigeminal ganglion cells back-labeled from the rat dura mater that is accompanied by increased levels of CGRP in the blood following exposure of sensitized rats to stress or an NO donor (45,46). Additionally, stress-induced or NO-donor induced allodynia is prevented by a CGRP antibody, consistent with efficacy demonstrated in humans with migraine (7). Collectively, these findings reveal the powerful neuroadaptive actions of therapeutics on the nervous system that are consistent with increased susceptibility to pain.

In conclusion, static measurements of pain thresholds are not necessarily sufficient to detect adaptive changes resulting from periods of drug exposure, but DNIC is a dynamic measurement of central pain modulatory circuits that can reveal neural adaptations that promote pain in response to exogenous stimuli or endogenous mechanisms (11). Several studies have assessed DNIC in migraine patients during the interictal phase (16,37 –42). To summarize these findings, a loss of DNIC was reported in episodic migraine patients in four out of seven of these studies (16,37 –42). One of these studies included a group of chronic migraine patients without MOH, and two included MOH patients; a loss of DNIC was found in all three of these patient groups, although one study of MOH patients found that the loss of DNIC occurred before medication withdrawal whereas the other found a loss of DNIC after withdrawal (16,38,39). In contrast, only one of these studies found a significant difference in response to the static measurement of the test stimulus alone, taken prior to DNIC testing, in migraine patients compared to healthy controls (16). Similarly, in the current study, rats that had a loss of DNIC on day 21 did not have altered responses to the test stimulus prior to DNIC testing. This suggests that, outside of acute attacks, dynamic measurements of pain may be more informative for the assessment of chronic pain syndromes, particularly those that occur with transient or paroxysmal episodes of pain, and that do not have a known origin including migraine, MOH, and other functional pain disorders. The combination of repeated pain attacks may act together with medications to increase the risk of future attacks and the development of MOH in individuals with migraine. Notably, mechanisms that inhibit enhanced descending facilitation may be relevant as targets for the development of new treatments to prevent the development of chronic functional pain, or possibly for recovery from sensitized states by promoting return to a physiological balance of descending pain modulation.

Key findings

Overuse of triptans or opioids can produce medication overuse headache (MOH) in some patients, a condition that is often characterized by a loss of conditioned pain modulation/diffuse noxious inhibitory controls (CPM/DNIC).

Opioid-induced hyperalgesia (OIH) was observed in male rats following 7 days of continuous morphine treatment via osmotic minipumps and was accompanied by a loss of DNIC. In contrast, no hyperalgesia or loss of DNIC was observed in sumatriptan-treated rats.

No loss of DNIC response was detected two weeks following termination of morphine or sumatriptan treatment (i.e. day 21) in rats that had not received prior nociceptive stimuli.

However, in morphine- or sumatriptan-primed rats, exposure to a noxious stimulus on day 7 produced a loss of the DNIC response on day 21, likely representing interictal loss of DNIC.

Exposure to anti-migraine drugs can promote a sensitized state that is revealed by dynamic assessment of descending pain modulatory circuits. Dysregulation of descending modulatory circuits by overuse of medications may increase the probability of future migraine episodes as well as the risk of MOH in individuals with migraine.

Footnotes

Acknowledgements

We thank Nathan Eyde and Pablo Hernandez for their technical assistance.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from the National Institutes of Health (NS106902 and DA041809).

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Sustained exposure to acute migraine medications combined with repeated noxious stimulation dysregulates descending pain modulatory circuits: Relevance to medication overuse headache

Abstract

Background

Methods

Results

Conclusions

Keywords

Introduction

Methods

Results

Morphine, but not sumatriptan, produces mechanical hyperalgesia

Loss of DNIC occurs both on day 7 during OIH, as well as following resolution of hyperalgesia at day 21

Morphine priming alone is not sufficient to cause a loss of DNIC on day 21 without the prior capsaicin “second hit” on day 7

High, but not low, dose sumatriptan priming followed by exposure to a capsaicin second hit produces a loss of DNIC on day 21

Sumatripan priming alone is not sufficient to cause loss of DNIC on day 21

Discussion

Key findings

Footnotes

Acknowledgements

Declaration of conflicting interests

Funding

References