Abstract
Background and aims
We have previously reported that systemic administration of sinomenine produced antinociception in various experimental pain conditions in rodents, particularly in models of neuropathic pain. In the present study we assessed the effects of repeated administration of sinomenine in two rodent models of neuropathic pain in order to study the development of tolerance.
Methods
The analgesic effect of sinomenine was tested in female Sprague-Dawley rats that exhibited mechanical and cold hypersensitivity following ischaemic injury to the spinal cord and in male C57/BL6 mice that developed mechanical hypersensitivity after ischaemic injury to the sciatic nerve. Briefly, the animals were anaesthetized and injected i.v. with the photosensitizing dye erythrosine B. Vertebral segments T12 to T13 in rats or the sciatic nerve in mice were exposed and irradiated under an argon ion laser for 10min or 45s, respectively. In rats, mechanical hypersensitivity to pressure with von Frey hairs, the response to brushing and decreasing cold temperature were tested in the flanks or upper back areas. In mice, mechanical hypersensitivity on the hind paw to von Frey hairs and response to cold following a drop of acetone were measured. Sinomenine was administered i.p. in rats and p.o. in mice at 10:00 and 16:00, twice a day for 5 days. Response threshold before and 2h after drug administration at 10.00h was recorded.
Results
Repeated administration of sinomenine at 10 or 20mg/kg twice a day, doses that have no analgesic effect as single injection, alleviated mechanical, but not cold allodynia in spinally injured rats and the effect was maintained during the 5 day treatment period with no signs of tolerance. Furthermore, the pre-drug response threshold was significantly elevated during repeated treatment with 20mg/kg sinomenine. Sinomenine administered at 40mg/kg twice a day for 5 days significantly reduced mechanical and cold alldoynia, elevated pre-drug response threshold without tolerance development in spinally injured rats. Similarly, sinomenine at 80mg/kg twice a day for 5 days significantly reduced mechanical allodynia in mice with sciatic nerve injury and increased pre-drug response threshold with no sign of tolerance. The effect of sinomenine on response threshold persisted for days after termination of the 5 day drug administration.
Conclusions
The results suggest that repeated administration of simomenine produced an enhanced anti-allodynic effect without tolerance in rodent models of neuropathic pain.
Implications
Sinomenine may be tested as a novel analgesic in treating some forms of chronic neuropathic pain in patients.
1 Introduction
In the European Union the prevalence of chronic pain is around 20% in adults and imposes a huge burden on society [1]. Chronic neuropathic pain that occurs after injury or disease in the central or peripheral nervous system causes a great reduction of life quality in patients [2]. However, the lack of adequate treatments of neuropathic pain remains problematic. The first line drugs used to treat neuropathic pain, such as pregabalin or gabapentin, only produce partial pain relief in a subset of patients [3, 4,5]. Opioid analgesics are ineffective against neuropathic pain in the majority of patients and are often associated with side effects including constipation, tolerance and drug abuse [6,7].
Traditional Chinese medicines (TCM) are widely used for management of various clinical pain conditions in China and may harbour a rich source of potential drug candidates, which Western drug companies are turning to with ever increasing urgency [8]. Sinomenine is a morphine derivative alkaloid purified from the root of the climbing plant Sinomenium Acutum. Sinomenine is traditionally used as a remedy for rheumatism and arthritis (RA) in Asia. Clinical research in dicated that compared with NSAIDs, sinomenine was more effective in ameliorating morning stiffness, painful joints and erythrocyte sedimentation rate in RA patients[9].Inaddition to possible pain relieving effect in RA, sinomenine has been suggested to be effective in some types of neuralgia, such as sciatic neuritis and lumbalgia, based mostly on anecdotal evidence [10].
In searching for effective components in TCMs for treating chronic pain, we have recently studied the effect of sinomenine in models of acute and chronic pain in rodents. Sinomenine appears to be particularly effective against neuropathic pain after injury to both the peripheral and central nervous system. In the present study, we evaluated the analgesic effect of sinomenine upon repeated administration on neuropathic pain using two rodent models, photochemically-induced spinal cord injury in rats [12], and sciatic nerve injury in mice [13].
2 Methodology
2.1 Animals
All experiments were approved by the regional research ethics committee. We used female Sprague-Dawley rats (Harlan, Horst, The Netherlands) weighing 300–350g, and male C57BL/6 mice, (Charles River, Sollentuna, Sweden) weighing 25–30g. The rats and mice were housed 4 or 6 per cage respectively at a constant room temperature of 22°C in a 12:12h light–dark cycle with ad libitum access to food and water.
2.2 Photochemically-induced spinal cord injury in rats
The method of producing photochemically induced spinal cord ischaemic injury in rats has been described in detail previously [12]. Briefly, the rats were anesthetized with 75mg/kg ketamine + 1mg/kg medetomidine and a midline incision was made in the skin overlying vertebral segments T12-L1. Following i.v. injection of 32.5 mg/kg of the photosensitizing dye erythrosine B (Sigma-Aldrich), vertebral segment T12 or T13 (spinal segments L3-5) was irradiated with an argon ion laser (Coherent) for 10min. A second dose of erythrosin B was injected 5min after the start of irradiation. During irradiation, the temperature of the animals was maintained 37–38°C.
2.3 Behavioural tests in rats
The threshold to mechanical stimulation was tested by gently restraining the animals in a standing position and calibrated von Frey hairs (Stoelting, Chicago, IL, USA) were applied to the shaved flanks or upper back areas. The von Frey hairs were applied 5–10 times at each intensity, with the frequency of 1/s. The stimulus which induced consistent vocalization (to >75% of stimuli) was considered as vocalization threshold. The cut-off value was 100 g.
For examining the response to brush stimuli, the skin on the flanks was briskly stroked with the point of a pencil in a rostral to caudal direction [14]. The response of the animals was graded with a score of 0 = no response, 1 = moderate efforts to avoid the probe but no vocalization, 2 = clear avoiding behaviour to the stimulus with transient vocalization, and 3 = vigorous efforts to avoid the stimulus, sustained vocalization in response to the probe.
Cooling stimuli were applied with a Peltier thermode to the flank [15]. A fluid cooled, hand held Peltier thermode (active surface: 25 mm × 50 mm, control resolution: >0.02°C, calibration uncertainty: ±0.2 °C) connected to a Modular Sensory Analyzer Thermal Stimulator (Somedic, Sweden) was used. The baseline temperature was 32 °C and the rate of temperature change was 0.5°C/s. Rats were held gently in a standing position and the thermode was pressed against the shaved flank area. Three cooling stimuli were applied at 1 min intervals and the average temperature at which the rats vocalized was taken as cold response threshold with 6°C as cut-off temperature.
2.4 Photochemically induced sciatic nerve injury in mice
The detailed method for producing ischaemic injury to the sciatic nerve in mice has been described previously [13]. Briefly, the animals were anaesthetized with 75 mg/kg ketamine+1mg/kg medetomidine and the left sciatic nerve was exposed. After i.v. injection of 32.5 mg/kg erythrosine B the sciatic nerve was irradiated under an argon ion laser for 45 s.
2.5 Behavioural test in mice
The withdrawal threshold of the ipsilateral hind paw to mechanical stimulation after sciatic nerve injury was tested using a set of calibrated von Fray hairs as described above. The response to cold after nerve injury was tested using a drop of acetone applied to the plantar surface of the hind paw ipsilateral to the nerve injury. The immediate response after acetone application was observed and scored as follows: 0 = no responses; 1 = startle response without evident paw withdrawal, 2 = withdraw of the stimulated hind paw, 3 = sustained withdraw of the simulated hind paw with flitching or licking.
2.6 Drugs
For preparation of sinomenine (obtained from The National Institute for Food and Drug Control, Beijing, China) for injection it was first dissolved with DMSO (Sigma-Aldrich), then mixed with Cremophor EL oil (Sigma-Aldrich) and saline by a vortex mixer (Bibby Scientific, UK) using the volume rate of 1:4:5. Any further dilution was made with saline. Sinomenine was administered i.p. in rats and orally in mice. To perform oral administration, the mouse was held in an upright standing position and a bulb tipped gastric gavage needle was used to deliver the sinomenine solution into the stomach by the attached syringe. Sinomenine was administered twice daily for 5 days at 10:00 hand 16:00 h. Baseline sensitivity to mechanical and cold stimuli was assessed before the administration of sinomenine at 10:00 h and two hours later, when sinomenine’s effect was maximal [11]. Control groups of spinal cord injured rats and sciatic nerve injured mice were administered saline twice a day for 5 days.
2.7 Statistics
The experiments were conducted blindly wherever a control group was included. Data are presented as mean±SEM or median±MAD, andwere analyzed by ANOVA with repeated measures and the Kruskal–Wallis test followed by Bonferroni/Dunn post hoc test, Wilcoxon signed rank test, or paired t-test. P< 0.05 is considered to be statistically significant.
3 Results
3.1 Effect of repeated administration of sinomenine on pain-like behaviours in spinally injured rats
As previously reported, rats developed chronic hypersensitivity to mechanical (von Frey hair and brushing) and cold stimuli after spinal cord injury [16,17]. The pharmacological experiments were conducted at 8 weeks following injury when hypersensitivity was maximal and stable.
Saline had no effect on either mechanical (Figs. 1A and 2A) or cold (3A) sensitivity. A single dose of i.p. sinomenine at 10 or 20mg/kg had no effects on responses to mechanical or cold stimulation in SCI rats (Figs.1B–D, 2B–Dand3B–D) aspreviouslyreported [11]. In contrast, repeated administration of 10mg/kg sinomenine twice per day elevated vocalization threshold to mechanical stimulations and reduced response score to brushing from day 2 to day 5 of treatment (Figs. 1B and 2B). However, repeated 10mg/kg sinomenine had no effect on hypersensitivity to cold (Fig. 3B).
Repeated administration of sinomenine at 20mg/kg reduced mechanical hypersensitivity to stimulation with von Frey hairs and brushing from day 2 to day 5 (Figs. 1C and 2C). Furthermore, pre-drug response threshold to von Frey hairs was significantly elevated from day 2 of sinomenine treatment and the threshold remained significantly elevated compared today 1 forat least 4 days after the cessation of drug application (Fig. 1C). The pretreatment response score to brushing was also significantly decreased from day 4 to day 6 after the start of drug treatment (Fig. 2C). However, 20mg/kg sinomenine did not alleviate allodynia to cooling (Fig. 3C).
Sinomenine administered twice/day at 40mg/kg effectively reduced mechanical hypersensitivity. Baseline thresholds to stimulation with von Frey hairs was significantly increased from day 2 of treatment and lasted until day 9, 4 days after the last administration of sinomenine (Fig. 1D). The response threshold returned to pre-sinomenine baseline level on day 12 (Fig. 1D). Hypersensitivity to brushing was also reversed on days 2, 4 and 5 following repeated sinomenine (Fig. 2D). The threshold temperature for cold stimulation was significantly decreased (indicating a decrease in cold hypersensitivity) 2 h after sinomenineduring the first two days (Fig. 3D). The pre-drug cold response temperature was significantly reduced from baseline level from day 2 to day 9 (Fig. 3D), again suggesting a sustained reduction in cold hypersensitivity.
In general, sinomenine dose-dependently suppressed hyper-sensitivity to mechanical (Fig. 1) and cold (Fig. 3) in rats after spinal cord injury.
3.2 Effect of repeated sinomenine on neuropathic pain-like behaviours in mice following sciatic nerve injury
Saline had no effect on paw withdrawal thershold (Fig. 4A) or cold (Fig. 4C). Sinomenine at 80mg/kg administered p.o.twice a day for 5 day sproduced significantly increased paw withdrawal threshold on days 1–5 (Fig. 4B). There was also a significant and persistent elevation in pre-drug baseline response threshold to simulation with von Frey hairs from day 2 and was maintained for 7 days after the termination of drug treatment (Fig. 4B). Sinomenine also significantly reduced mechanical and cold post-drug responses, in comparison with the pre-drug thresholds (Fig. 4B and D).
4 Discussion
We have previously reported that a single dose of sinomenine alleviated pain-like responses in spinal cord injured rats at or above 40mg/kg [11]. In the present study we showed that repeated administration of sinomenine even at 10mg/kg reduced mechanical allodynia-like responses in spinal cord injured rats after the third injection and the effect was maintained during the 5 day treatment with no signs of tolerance. Repeated administration of sinomenine at 20 or 40mg/kg not only reduced mechanical allodynia-like responses without tolerance, but also significantly increased pre-drug baseline response threshold after two injections. The increase in pre-drug response thresholds for the response to brush were maintained during the 5 day administration of sinonemine at 10 or 40mg/kg doses and maintained up to day 6 following the last 20mg/kg dose.
Similar effects were observed in a mouse model of neuropathic pain after sciatic nerve injury in which 80mg/kg sinomenine, an effective dose on its own [11], produced marked anti-allodynic response against mechanical stimulation after repeated injections for 5 days without producing tolerance. Furthermore, as in rats with spinal cord injury, we observed a significant increase in pre-drug response threshold after two injections which was maintained to day 12, 7 days after the termination of drug administration. In both rats and mice, sinomenine appears to be less effective against cold than mechanical hypersensitivity, which is similar to our previous results [11].
We found that a single i.p. administration of sinomenine at 20 and 40mg/kg produced little or no side effects, and 80mg/kg simonemine caused some sedation in rats [11]. In the present study no side effects (sedation, motor impairment or irritation) were observed during or after repeated sinomenine administration. Previous studies in rats have also suggested that daily administration at 40 or 80mg/kg for two weeks did not influence growth, appetite and blood pressure [18]. There were also no apparent withdrawal symptoms following the termination of drug treatment in the present study. These observations, together with the fact that no tolerance to the anti-allodynic effects of sinomenine was observed after repeated administration, suggest that sinomenine may be useful to treat chronic neuropathic pain.
The effects of repeated sinomenine on neuropathic pain like behaviours in our models are similar to the effect of the anti-epileptics lacosamide and gabapentin [19, 20,21]. In particular, the analgesic effect of gabapentin was also increased following repeated administration at doses that were ineffective as a single injection [19]. Moreover, repeated lacosamide alleviated pre-drug baseline responses, similar to that of sinomenine [20]. In contrast, i.p. morphine did not alleviate allodynia in rats with spinal cord injury. Intrathecal morphine did have some anti-allodynic effect, but tolerance was observed after 2 days of twice daily treatment [22].
One of the remarkable effects of sinomeninein these two rodent models of neuropathic pain is that it reduced baseline hypersen-sitivity following repeated administration, resulting in persistent reduction in allodynia. Since sinomenine has a relatively short half-life in rat plasma [23,24], it is unlikely that this effect is due to an accumulation of the drug following repeated injections. Some of the anti-allodynic effects of sinomenine may be mediated by its metabolites which are known to be present in at least three forms [25]. However, it is unknown whether these metabolites are pharmacologically active. Alternatively, the effects of repeated sinomenine may reflect sustained physiological changes resulting from repeated drug treatment. Such changes are, however, reversible and may require continuous drug treatment since allodynia recurred within days following the last dose of sinenomine.
The mechanisms for the anti-allodynic effect of sinomenine in models of neuropathic pain are not clear. We have previously shown that the anti-allodynic effect of sinomenine was not reversed by the opioid receptor antagonist naloxone [11] and the profile of analgesia produced by sinomenine is different from that of systemic morphine [22,26]. In contrast, the effect profile of sinomenine is similar to that of dextromethorphan, a non-opioid antitussive that is an weak noncompetitive NMDA receptor antagonist [11,27]. Sinomenine is structurally related to levorphanol and dextromethorphan and is also antitussive [18]. Although there is currently no evidence that sinomenine can function as an NMDA receptor antagonist, it does have a neuroprotective effect possibly mediated by blocking of acid-sensing ion channel and calcium channels [28]. Furthermore, repeated administration of sinomenine delays tolerance to morphine [29,30], which is also observed with dextromethorphan [31].
One of the possible mechanisms for the anti-allodynic effect of chronic sinomenine may be related to its ability to modulate neurotransmitter release in the spinal cord and brain. Systemic sinomenine alters the level of monoamines in extracellular fluid in the striatum in rats after sciatic nerve injury with increase in the level of noradrenaline and decrease in level of dopamine and serotonin [32]. These effects are correlated with analgesic effect of sinomenine 32]. Chronic sinomenine may produce long term effects on transmitter synthesis and neuronal functions through altered transmitter release.
Sinomenine also has distinct immunoregulatory and neuroprotective properties. It can reduce the production of COX-2 dependent Prostaglandin E2 [33], block NF-κB and p38MAPK signal pathways [34,35], and reduce microglia activation by inhibiting NADPH oxidase [36]. It is conceivable that some of these properties of sinomenine may reduce neuronal sensitization in the peripheral and central nervous system and contribute to its analgesic effects in neuropathic pain.
5 Conclusion
In conclusion, the present results showed that the anti-allodynic effect of sinomenine upon repeated chronic administration did not lead to tolerance, but rather enhanced its effect, in two rodent models of neuropathic pain, resulting in a persistent, but reversible, analgesia with no observable side effects.
6 Implications
The results from this research may suggest potential clinical application of sinomenine as a novel analgesic in treating chronic neuropathic pain.
Highlights
Spinally injured rats and sciatic nerve injured mice were used to study the effect of repeatedly administered sinomenine on hypersensitivity to mechanical and cold stimuli.
Following repeated administration, the analgesic effect of sinomenine was increased, without development of tolerance
Sinomenine may be explored as a novel analgesic for treating some forms of chronic neuropathic pain in patients.
DOI of refers to article: http://dx.doi.org/10.1016/j.sjpain.2014.08.002.
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Conflict of interest: We declare no conflicts of interests.
Acknowledgement
This study was supported by Swedish Science Council (Proj. 12168), the Swedish Foundation for Strategic Research, research funds of the Karolinska Institutet and International S&T Cooperation (Proj. 2010DFA31890).
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