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Abstract

Aim

Evaluation of cannabinoid receptor agonists in a preclinical model of medication overuse headache.

Methods

Female Sprague Dawley rats received graded intraperitoneal doses of WIN55,212-2 or Δ-9-tetrahydrocannabinol (Δ-9-THC). Antinociception (tail-flick test), catalepsy and hypomotility (open field test) and impairment of motor function (rotarod test) were assessed to establish effective dosing. Rats were then treated twice daily with equianalgesic doses of WIN55,212-2 or Δ-9-THC, or vehicle, for 7 days and cutaneous tactile sensory thresholds were evaluated during and three weeks following drug discontinuation. Rats then received a one-hour period of bright light stress (BLS) on two consecutive days and tactile sensory thresholds were re-assessed.

Results

WIN55,212-2 and Δ-9-THC produced antinociception as well as hypomotility, catalepsy and motor impairment. Repeated administration of WIN55,212-2 and Δ-9-THC induced generalized periorbital and hindpaw allodynia that resolved within 3 weeks after discontinuation of drug. Two episodes of BLS produced delayed and long-lasting periorbital and hindpaw allodynia selectively in rats previously treated with WIN55,212-2, and Δ-9-THC.

Interpretation

Cannabinoid receptor agonists including Δ-9-THC produce a state of latent sensitization characterized by increased sensitivity to stress, a presumed migraine trigger. Overuse of cannabinoids including cannabis may increase the risk of medication overuse headache in vulnerable individuals.

Keywords

Migraine medication overuse headache cannabis Δ-9-THC sensitization stress

Introduction

Medication overuse headache (MOH) is diagnosed in patients with pre-existing headache disorders as a new headache or significant worsening of a pre-existing headache as a consequence of regular overuse of acute headache medication for 10 or 15 days per month for more than 3 months (1,2). Triptans, and opioid use primarily in the United States, are associated with increased risk of MOH following 12 or 8 doses per month, respectively (1, 3 –5). MOH has a worldwide population prevalence of 1.5–3.0% and occurs in 11–70% of patients with chronic headache (6 –8). MOH is also highly disabling. According to the global burden of disease report, MOH is the 18th leading cause of years lived with disability (9). The mechanisms involved in the development and maintenance of MOH are not completely understood and novel effective acute anti-migraine therapies with reduced risk of MOH development are highly desirable (1,3,5).

Cannabinoids, including those found in marijuana, have been proposed as effective and safe for the acute treatment of migraine (10 –12). Delta-9-tetrahydrocannabinol (Δ-9-THC) is a primary active component of marijuana (13). Pharmacologically, Δ-9-THC acts as a partial agonist of the cannabinoid CB1 receptor, one of the most widely expressed G-protein coupled receptors in the mammalian brain (13 –15). The CB1 receptor is found on primary afferent nociceptors, in the spinal dorsal horn and in supraspinal circuits that are associated with the modulation of pain (16). Antinociceptive effects of Δ-9-THC and synthetic cannabinoids, including WIN55,212-2, have been reported in preclinical studies (10,11,17 –19). Clinical studies demonstrating analgesic actions of marijuana and synthetic cannabinoids, however, have been less certain (13,20,21). Strong evidence for analgesia remains limited to pain in patients with multiple sclerosis (MS) that might arise, in part, from relief of spasticity (22,23). Nevertheless, cannabinoids including medical marijuana are widely used for pain control either with, or without, prescriptions from physicians. Electronic questionnaires reveal that marijuana is a common method of self-medication or a substitution option for analgesics used for the treatment of migraine (10,11). Headache attacks resulting from cannabis have been reported previously (24).

The effects of long-term use or overuse of cannabinoids, especially in vulnerable individuals, remain unknown (13,25). A particular concern may be that people with pre-existing migraine may develop MOH following overuse of marijuana for pain control or for recreational purposes. We have developed a model of MOH in rats following a period of exposure to triptans or opioids that is characterized by latent sensitization of trigeminal sensory pathways to typical migraine triggers including stress or nitric oxide donors (3,26 –28). The present study was designed to explore the possibility that exposure to cannabinoids could, like many acute migraine medications, result in latent trigeminal sensitization and vulnerability to typical migraine triggers. In rodents, cannabinoid effects are typically assessed by the “tetrad” test, consisting of drug-induced hypomotility, catalepsy, hypothermia and antinociception (29). We examined the effects of WIN55,212 and Δ-9-THC, full and partial CB1 agonists (30,31), respectively (13,15), in eliciting typical rodent cannabinoid effects and then determined if equianalgesic doses of these compounds could elicit the characteristics of MOH as established in our preclinical model and similar to what has been demonstrated with triptans and opioids.

Methods

Animals

Adult, female Sprague Dawley rats, 225–250 g (Harlan Laboratories, Indianapolis, IN) were used in these studies. Rats were housed three per cage in climate- and humidity-controlled conditions, 12/12 h light/dark cycle (lights on at 7am – 7pm), with food and water ad libitum. A total of 249 animals were used in these studies with 5–15 animals per group size for evaluation of behavior. Experimenters were blinded to the conditions in all behavioral assays performed in these studies and rats were randomly divided into control and experimental groups. All experimental procedures were conducted in accordance with the ARRIVE guidelines, with the ethical guidelines of the International Association for the Study of Pain regulations on animal welfare and the National Institutes of Health guidelines for the care and use of laboratory animals. The procedures were previously approved by the Institutional Animal Care and Use Committee of the University of Arizona. All efforts were made to reduce the number of animals used and their suffering in these studies.

Drugs

All drugs were given intraperitoneally (i.p.) at a volume of 1 mL/kg. WIN55,212-2 mesylate (TOCRIS, Minneapolis, MN, USA) was diluted in 10% DMSO, 10% TWEEN 80 and 80% PBS (Sigma Aldrich, San Francisco, USA). Delta-9-tetrahydrocannabinol (Δ-9-THC, Cayman Chemical Company, Ann Arbor, MI, USA) was dissolved in 5% ethanol, 5% cremophor, 90% PBS (Sigma Aldrich, San Francisco, USA). Controls received 1 mL/kg injection of the respective vehicle.

Tail-flick assay

Rats were gently held by the experimenter, and half of the distal tail was immersed in a constant 50℃ circulating hot-water bath (Neslab Instruments, Inc, Newington, NH). The latency of the response to the stimulation was characterized by the time (seconds) required for animals to flick their tail. A cutoff of 15 seconds was established to avoid tissue damage.

Catalepsy evaluation

The forelimbs of the rat were gently placed on a 1.4 cm diameter horizontal cylindrical Plexiglas bar at a height of 10 cm with the hindlimbs on the floor. The latency from the time of setting the animal's forepaw on the bar until one forepaw touched the floor, or the hindpaws left the floor to climb onto the bar, was recorded. A cut-off time of 300 s was used for animals that did not make movements of forepaws or hindpaws.

Rotarod test

Rats were trained to walk on the automated rotarod device (Columbus Instruments International, Columbus, OH) in two training sessions, as previously described (32). The training sessions consisted of placing the animals on the apparatus until they could remain on the device set at a continuous speed of 10 revolutions per minute for a duration of 180 s. One day after training, rats were tested for their baseline performance and then retested after administration of WIN55,212-2 or Δ-9-THC. The latency to fall was determined before and 15, 30, 60 and 120 min after the treatment, with a maximum cutoff time of 180 s for each evaluation.

Open field assay

Animals were placed into a large, uncovered Plexiglas cubic box, measuring 47 cm³. The bottom of the box was divided into nine even squares. Rats were injected with either WIN55,212-2, Δ-9-THC or vehicle and after 30 min, placed into the center of the box to freely explore the arena for 5 min. Behavior was recorded by a video camera (Logitech C270 HD Webcam) positioned directly above the box. The number of square crossings, vertical rearing and total distance traveled were assessed.

Evaluation of periorbital and hindpaw tactile sensory thresholds

Periorbital and hindpaw tactile sensory thresholds were evaluated prior to, and after repeated administration of WIN55,212-2 or Δ-9-THC. Rats were placed individually in suspended clear Plexiglas chambers with wire mesh floors for 1 h to habituate before testing. The tactile threshold was measured by the perpendicular application of a series of calibrated von Frey filaments (Touch Test sensory evaluators; Stoelting, Wood Dale, IL) applied to the periorbital region, at the center of the forehead, or the plantar surface of the hindpaw until a withdrawal response was elicited. Cutoff was set at 8 or 15 g for periorbital or hindpaw regions, respectively, as previously reported (33). The up and down methodology was applied to determine withdrawal threshold as previously described (34).

Environmental bright light stress

Rats were placed in Plexiglass cages and received two episodes of bright light stress (BLS) on days 27 and 28 post-drug injection as described previously (35). These time points were chosen to ensure that after discontinuation of repeated drug administration, sensory thresholds had returned to baseline levels. BLS was induced by two LED lights that were placed on both sides of the cage to deliver approximately 1400 lux for 1 h each day.

General experimental design overview

In all experiments, control groups included animals dosed with the respective diluents for WIN55,212-2 or Δ-9-THC. As no significant differences were observed between the respective vehicle groups, the data were pooled. The antinociceptive effect of WIN55,212-2 and Δ-9-THC treatment on the tail-flick test was assessed using a 50℃ water bath as the nociceptive stimulus in different cohorts of rats. Baseline nociceptive reflex response was recorded and followed by a single i.p. administration of WIN55,212-2 at 0.3, 1 and 3 mg/kg, or Δ-9-THC at 0.32, 1 and 3 mg/kg. Tail-flick withdrawal latency was reassessed after 15 and 30 min and every hour for up to 5 h after treatment. These doses were also used to assess classical cannabinoid effects on catalepsy, open field and rotarod tests. Animals were tested 30 min following i.p. injection of WIN55,212-2, Δ-9-THC or vehicle in sequence for catalepsy followed by the open field test. WIN55,212-2 and Δ-9-THC or vehicle were assessed for effects on rotarod in animals previously trained on this device.

To evaluate the possible development of cutaneous allodynia after repeated injections of WIN55,212-2 and Δ-9-THC, periorbital and hindpaw thresholds were evaluated prior to the treatment, for the determination of baseline thresholds, followed by twice daily (9 am and 5 pm) injections for 7 consecutive days. A dose of 3 mg/kg was chosen for both drugs, as they produced approximately equivalent maximal antinociceptive effects. Periorbital and hindpaw tactile sensory thresholds were evaluated on days 7, 10, 14, 18, 21 and 28 after the first treatment. On day 27, when sensory thresholds had recovered to baseline levels, animals received one BLS exposure for 1 h. On day 28, periorbital and hindpaw tactile sensory thresholds were evaluated and followed by a second BLS exposure for 1 h. Tactile sensory thresholds were then assessed hourly for 5 h.

Statistical analysis

Sample size was calculated using the GPower 3.1 software, with an established significance level of p < 0.05. Statistical analyses used in these studies were calculated using GraphPad Prism 7 (GraphPad Software, La Jolla, CA). Two-way analysis of variance (ANOVA) followed by the Sidak or Tukey test were used for analysis of the time course experiments for tail-flick, rotarod and sensory thresholds for two or more than two groups comparisons, respectively. One-way analysis of variance (ANOVA) followed by the Tukey test was used to analyze the number of crossings, rearing and total distance on open field test and catalepsy evaluation. One-way analysis of variance (ANOVA) was also used to analyze the tactile thresholds of the vehicle-treated group evaluated each day, plotted as a bar graph with one separate bar representing each day of evaluation. The numbers of animals used (n), p values and F ratios are reported below. All data are presented as mean ± SEM and statistical significance was set at p < 0.05.

Results

Dose-dependent antinociceptive effects of WIN55,212-2 and Δ-9-THC

All three doses of WIN55,212-2 (0.3, 1 and 3 mg/kg) elicited time- and dose-related antinociception measured by increased latency to tail-flick response in comparison to the vehicle-treated group. The lower doses were effective for 1 h after treatment, while the higher dose induced antinociception for 4 h after treatment (Figure 1(a); p < 0.0001; F (21, 315) = 8.15). Treatment with Δ-9-THC also produced antinociception in comparison to the vehicle-treated group at 1 and 3 mg/kg, i.p., up to 1 and 4 h after the treatment, respectively (Figure 1(b); p < 0.0001; F (21, 315) = 17.16). Maximal antinociceptive effects were observed for both drugs at a dose of 3 mg/kg. Intraperitoneal treatment with Δ-9-THC at 0.32 mg/kg had no significant effects on tail withdrawal latencies (Figure 1(b); p > 0.05).

Figure 1.

Antinociceptive dose- and time-response for WIN55,212-2 and Δ-9-THC on tail-flick assay in female rats. Baseline tail withdrawal latencies to thermal heat (50℃ water bath) were determined before and after intraperitoneal treatments. WIN55,212-2 treatment at 0.3, 1 and 3 mg/kg (a) and Δ-9-THC treatment at 1 and 3 mg/kg (b) significantly increased tail withdrawal latency when compared with vehicle-treated animals (n = 6–11). Lower dose of Δ-9-THC did not alter the tail-flick response during the time of evaluation. Maximal antinociceptive effects were observed with the highest doses of WIN55,212-2 and Δ-9-THC ((a) and (b)). Data are presented as mean ± SEM and were analyzed using two-way ANOVA followed by Tukey test for multiple comparisons.

Higher doses of WIN55,212-2 and Δ-9-THC induce catalepsy

Both WIN55,212-2 (Figure 2(a); p < 0.01; F (3, 48) =4.546) and Δ-9-THC (Figure 2(b); p < 0.0001; F (3, 42) =9.967) produced catalepsy at 3 mg/kg. The catalepsy produced by WIN55,212-2 was, however, more robust than observed with Δ-9-THC (Figures 2(a) and (b)). Lower doses of WIN55,212-2 and Δ-9-THC had no significant effect on the catalepsy test (Figure 2(a) and (b); p > 0.05).

Figure 2.

High doses of WIN55,212-2 and Δ-9-THC intraperitoneal treatment induced catalepsy and decreased performance on rotarod test of female rats. WIN55,212-2 (a) and Δ-9-THC treatment (b), both at 3 mg/kg, significantly increased latency to remove the forepaw from the bars when compared with vehicle-treated animals (n = 6–11). WIN55,212-2 (c) and Δ-9-THC (d), both at 3 mg/kg, significantly induced motor activity deficit as demonstrated by the rat's decreased latency to fall on rotarod test when compared with vehicle-treated animals (n = 6–11). Lower doses of WIN55,212-2 and Δ-9-THC did not induce catalepsy and did not influence the animal's latency ((a), (b), (c) and (d)). For catalepsy and rotarod test, data are presented as mean ± SEM analyzed using one-way ANOVA or two-way ANOVA, respectively, followed by Tukey test for multiple comparisons.

WIN55,212-2 and Δ-9-THC induce hypomotility

Following evaluation in the catalepsy test, animals were immediately placed into the open-field arena for 5 min. WIN55,212-2 at 1 and 3 mg/kg reduced the number of crossings (Figure 3(a); p < 0.0001; F (3, 48) = 12.28), rearing (Figure 3(b); p < 0.0001; F (3, 48) = 32.98) and total distance traveled in comparison to vehicle-treated group (Figure 3(c); p < 0.0001; F (3, 48) = 11.87); no significant effects were observed at 0.3 mg/kg on these measures (Figure 3(a), (b) and (c); p > 0.05). Δ-9-THC at 0.32, 1 and 3 mg/kg reduced the number of rearings in comparison to vehicle-treated animals (Figure 3(e); p < 0.001; F (3, 42) = 8.321). Δ-9-THC had no significant effects on the number of crossings and total distance traveled on the open-field test at the doses tested (Figure 3(d) and (f); p > 0.05).

Figure 3.

WIN55,212-2 and Δ-9-THC induce hypomotility in the open field test. Motor activity was performed in an open field arena with number of crossings, rearing and total distance traveled analyzed. Intraperitoneal administration of WIN55,212-2 at 1 and 3, but not 0.3 mg/kg, significantly decreased the number of crossings (a), rearing (b) and total distance (c) when compared with the lower dose of WIN55,212-2 and vehicle-treated animals (n = 10–15). Intraperitoneal administration of Δ-9-THC at 0.32, 1 and 3 mg/kg significantly decreased the number of rearings (e) when compared with the vehicle-treated animals (n = 10–15). The number of crossings (d) or total distance traveled (f) were not affected by Δ-9-THC treatment. Data are presented as mean ± SEM analyzed using one-way ANOVA followed by Tukey test for multiple comparisons.

WIN55,212-2 and Δ-9-THC produce motor impairments

Both WIN55,212-2 (Figure 2(c); p < 0.0001; F (12, 100) = 13.8) and Δ-9-THC (Figure 2(d); p = 0.0410; F (12, 132) = 1.628) treatment at 3 mg/kg induced motor impairment, demonstrated by a decreased latency to fall from the rotarod device when compared to the vehicle-treated group. The effect of WIN55,212-2 was more robust than that of Δ-9-THC (Figures 2(c) and (d)). Lower doses of WIN55,212-2 and Δ-9-THC had no significant effect on the rotarod test (Figure 2(c) and (d), p > 0.05).

Figure 4.

WIN55,212-2 and Δ-9-THC induced latent sensitization with periorbital and hindpaw cutaneous allodynia evoked by bright light stress (BLS) in female rats. Intraperitoneal injections of WIN55,212-2 (a) and Δ-9-THC (b) were performed twice daily for 7 consecutive days. Periorbital and hindpaw tactile thresholds were evaluated prior to baseline (BL), and on days 7, 10, 14, 18 and 21 after the first cannabinoid treatment. Rats were then exposed to BLS for 1 h on days 27 and 28 after cannabinoid administration. At day 28, periorbital and hindpaw tactile thresholds were evaluated prior to baseline (BL), and hourly after BLS for up to 5 h. Repeated administration of WIN55,212-2 and Δ-9-THC induced hypersensitivity that resolved by day 27. Bright light stress reinstated hypersensitivity in WIN55,212-2 and Δ-9-THC-primed rats. Data are presented as mean ± SEM analyzed using two-way ANOVA followed by Tukey test for multiple comparisons.

WIN55,212-2 and Δ-9-THC administration produce generalized allodynia

Rats received twice daily WIN55,212-2 or Δ-9-THC, both at 3 mg/kg, for 7 consecutive days, at 9 am and 5 pm. Seven days of repeated injections of Δ-9-THC produced reductions in periorbital (Figure 4(a); p < 0.0001; F (22, 198) = 3.453) and hindpaw (Figure 4(b); p < 0.01; F (22, 198) = 1.927) withdrawal thresholds in comparison to the vehicle-treated group. Repeated administration of WIN55,212-2 did not produce statistically significant alteration of periorbital threshold but produced a reduction in hindpaw (Figure 4(b); p < 0.01; F (22, 198) = 1.927) withdrawal thresholds in comparison to the vehicle-treated group. Hindpaw thresholds remained lower than those of vehicle-treated animals for 21 days following the beginning of drug delivery but returned to baseline levels by day 27.

Prior exposure to WIN55,212-2 or Δ-9-THC produces sensitization to subsequent stress

Exposure to two episodes of BLS on days 27 and 28 produced reductions in periorbital (Figure 4(a); p < 0.0001; F (12, 108) = 4.916) and hindpaw (Figure 4(b); p < 0.01; F (12, 108) = 2.962) withdrawal thresholds only in rats that had been previously treated with WIN55,212-2 or Δ-9-THC. Significant reductions in periorbital and hindpaw withdrawal thresholds were detected at 1, 2 and 3 h and at 1 and 2 h post-stress, respectively, in animals previously treated with the cannabinoids. No significant changes in tactile thresholds were observed in the vehicle treated group (p > 0.05 for all time points compared to the pre-BLS baseline).

Discussion

Cannabis has been legalized for both medicinal and recreational purposes in Canada and approximately one in seven people in the US use cannabis with or without prescription to achieve pain relief, including for the acute treatment of migraine; the use of cannabis has been gradually increasing (10,11) and cannabis has been reported to promote cluster headache in some patients (24). For these reasons, the goal of this study was to assess the possibility that cannabinoids may promote medication overuse headache in a preclinical rodent model. As migraine has a predominant female prevalence (36), we evaluated the effects of these drugs in female rats.

Our previous studies have established that a period of exposure to either triptans or to opioids can result in a long-lasting state of “latent sensitization” in which injury-free animals are hyper-responsive to known, or presumed, migraine triggers including nitric oxide donors and stress (26 –28,37,38). Latent sensitization induced by triptans was accompanied by morphological and functional changes including an increase in the number of identified trigeminal ganglion cells that innervate the dura mater that express CGRP, as well as increased release of CGRP in the blood following challenge with NO donor or stress (27,37,38). Additionally, stress-induced allodynic responses were prevented by pre-treatment with TEV48125, a CGRP monoclonal antibody that is effective and approved by the Food and Drug Administration for the preventive treatment of migraine (37). The present study used this model to determine if WIN55,212-2, a high efficacy CB1 agonist, and Δ-9-THC, a principal component of marijuana that has been previously characterized as a partial agonist at CB1 receptors, could similarly induce a state of latent trigeminal sensitization in uninjured rats characterized by increased sensitivity to stress. Both cephalic and extra-cephalic allodynia have been observed during migraine attack (39). We evaluated both periorbital (cephalic) and hindpaw (extra-cephalic) allodynia in rats exposed to cannabinoids. Consistent with previous reports from our laboratory in studies with triptans and opioids (3,26,27), periorbital and hindpaw allodynia was observed, suggesting states of trigeminal and central sensitization. In addition, these periods of exposure with these cannabinoid agonists produced a long-lasting increased sensitivity to stress, supporting the possibility that sustained CB1 receptor activation may increase the risk of MOH in vulnerable populations, including those with migraine.

Preclinical assessment of CB1 receptor engagement in rodents is commonly based on the “tetrad” test, which includes drug-induced hypomotility, catalepsy, hypothermia and antinociception (29). Three of these outcome measures were used in the present study to establish doses of WIN55,212-2 and Δ-9-THC that would clearly elicit CB1 effects and to establish approximately equieffective antinociceptive doses, allowing comparison between these drugs. Consistent with previous reports, WIN55,212-2 and Δ-9-THC produced antinociception as well as hypomotility, catalepsy and motor impairment (29,40,41). Despite reported differences in efficacy of WIN55,212-2 and Δ-9-THC, we found that the same dose, 3 mg/kg, produced equivalent maximal antinociceptive responses and this dose was therefore used in the initial period of cannabinoid exposure.

In the present study, repeated injections of Δ-9-THC produced both cephalic and extra-cephalic allodynia, while WIN55,212-2 produced only extra-cephalic allodynia after the period of drug exposure. Our previous observations with triptans and opioids demonstrate that recovery of sensory thresholds to baseline levels takes approximately 2 weeks following termination of drug administration (27,28,37,38). However, the present study showed that cannabinoid-induced hindpaw allodynia persisted for a longer period of time and that 3 weeks were required for sensory thresholds to return to baseline levels. The longer duration of allodynia following exposure to these drugs is consistent with their highly lipophilic nature and it is well established that levels of Δ-9-THC are also detected for long periods of time in humans after use of marijuana (10,11,13). Following recovery of sensory thresholds to pre-drug baseline levels, BLS elicited delayed and generalized allodynia only in animals that were previously exposed to WIN55,212-2 or Δ-9-THC.

Allodynia is a prominent clinical symptom that has been observed in the majority of migraine patients during an attack, and may therefore represent an endpoint with translational relevance across species (42,43). The effect of pretreatment with WIN55,212-2 in stress-induced periorbital allodynia was more robust and longer-lasting than that observed following pretreatment with Δ-9-THC. This observation may be consistent with the respective full and partial agonist efficacy at CB1 receptors of WIN55,212-2 and Δ-9-THC that is revealed with repeated, rather than acute, administration (13,15). The data suggest that a period of exposure to these agonists, presumably relevant to overuse of these medications on a repeated basis, is associated with increased responsiveness to presumed migraine triggers and increased risk of development of MOH.

The association of cannabinoids with MOH has been observed anecdotally in the clinic and has been previously explored in one preclinical report. Kandasamy and colleagues administered repeated doses of Δ-9-THC or morphine to female rats and then determined the consequences of acute administration of these drugs in eliciting an antinociceptive effect (i.e. tolerance); antinociception was measured as reversal of suppressed wheel running elicited by dural application of AITC, a TRPA1 agonist (17,44). Their findings suggested that Δ-9-THC produced less antinociceptive tolerance than morphine (44). Furthermore, they found that repeated morphine, but not Δ-9-THC, pretreatment resulted in an extended duration of AITC-suppressed wheel running, a finding that was interpreted as indicative of MOH from morphine, but not Δ-9-THC (44). Multiple reasons may account for the different conclusions reached by our study, including the uncertain relevance of the output measure from Kandasamy and colleagues to MOH. Additionally, the reported lack of tolerance to the antinociceptive action of Δ-9-THC is inconsistent with previous reports with CB1 agonists (45) and may be related to the dose chosen for administration, the frequency of dosing, and a comparison of non-equivalent morphine and Δ-9-THC doses used in pretreatment. Another difference in our study is that here the effects of a presumed migraine trigger were assessed in a drug-free period following an initial “priming” period to induce latent sensitization. It should also be noted that even though opioids and triptans are associated with the development of MOH, they nevertheless are generally effective in the treatment of an acute migraine attack in migraine patients (5,46).

Reports of marijuana use for acute migraine treatment through self-medication or as a substitute for analgesics are increasingly common (10 –12,47). Medical marijuana has been reported to reduce the frequency of attacks in patients with migraine (19,48). The distribution of cannabinoid receptors is consistent with potential anti-migraine effects that have been reported in preclinical studies (16,17,49,50). Both brain and nociceptor expression of cannabinoid receptors might be relevant to reducing headache pain, and, in the trigeminal system, CB1 activation may inhibit the release of neuropeptides associated with migraine such as calcitonin gene-related peptide (CGRP) (51). Cannabinoids, including Δ-9-THC, might represent an acute anti-migraine strategy (10 –12,47,49,50). Nevertheless, these studies have not addressed the consequences of long-term use of marijuana or novel synthetic cannabinoid-derivate compounds referred to as “spices” that are 10–30 times more potent than the natural compounds (52 –54). Cannabinoid-induced hyperemesis syndrome, a condition that is characterized by repeated and persistent bouts of vomiting attacks has been observed (55). Of particular concern is that the overuse of marijuana or spices may lead to MOH in patients with migraine (52 –54). While many medications used for the treatment of migraine have been related to the development of MOH, the evidence is strongest for triptans and opioids (1,3,4). Opioids are known to produce plasticity in brain circuits that are characterized in preclinical studies by expansion of receptive fields, increased temporal summation, increased evoked transmitter release, hyperalgesia and allodynia. While less well characterized, triptans similarly produce allodynia and enhanced evoked transmitter release (3). We have also previously reported hyperalgesia with repeated cannabinoid administration though, unlike opioids, clinical reports of cannabinoid-induced hyperalgesia are rare (56). Additionally, cannabinoid receptor agonists have been reported to activate the hypothalamic-pituitary-adrenal (HPA) axis, which may promote responses to external stressors (57). Collectively, the data suggest that multiple mechanisms may exist to promote an increase in sensitivity to amplify sensory stimuli that are normally innocuous to elicit a pain attack, consistent with the conclusion that agonists at CB1 receptors may be associated with increased risk of MOH.

Conclusion

Cannabinoids are perceived to be analgesic in migraine but risks of overuse of medications containing Δ-9-THC or other components of marijuana remain uncertain. Consistent with previous observations with triptans and opioids, our study suggests that a period of repeated exposure cannabinoid CB1 agonists, including Δ-9-THC, induces MOH-like behaviors in female rats. While this study evaluated the effects of Δ-9-THC in inducing MOH, we note that cannabis contains more than 100 known cannabinoids so that these constituents might potentiate possible effects of Δ-9-THC in promoting MOH. Additionally, we note that the lipophilic nature of these drugs is likely to result in a long-term exposure at the receptor. Finally, cannabis has been reported to have negative effects in adolescents (58,59) raising questions about potential increased risk in younger populations who are susceptible to migraine.

Footnotes

Article highlights

Δ-9-THC and a synthetic cannabinoid agonist produced allodynic responses in uninjured female rats and increased sensitivity to an environmental stress.

Cannabinoid agonists may increase the risk of medication overuse headache in vulnerable individuals.

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 research was supported by P01 DA041307 (F.P.).

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Cannabinoids induce latent sensitization in a preclinical model of medication overuse headache

Abstract

Aim

Methods

Results

Interpretation

Keywords

Introduction

Methods

Animals

Drugs

Tail-flick assay

Catalepsy evaluation

Rotarod test

Open field assay

Evaluation of periorbital and hindpaw tactile sensory thresholds

Environmental bright light stress

General experimental design overview

Statistical analysis

Results

Dose-dependent antinociceptive effects of WIN55,212-2 and Δ-9-THC

Higher doses of WIN55,212-2 and Δ-9-THC induce catalepsy

WIN55,212-2 and Δ-9-THC induce hypomotility

WIN55,212-2 and Δ-9-THC produce motor impairments

WIN55,212-2 and Δ-9-THC administration produce generalized allodynia

Prior exposure to WIN55,212-2 or Δ-9-THC produces sensitization to subsequent stress

Discussion

Conclusion

Footnotes

Article highlights

Declaration of conflicting interests

Funding

References