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Keywords:

  • afferent;
  • cannabinoid;
  • immune;
  • mast cell;
  • neuron;
  • sensory

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Abstract  Cannabinoid 2 (CB2) receptors have both antinociceptive and antihypersensitivity effects, although the precise mechanisms of action are still unclear. In this study, the modulatory role of CB2 receptors on the mesenteric afferent response to the endogenous immunogenic agent bradykinin (BK) was investigated. Mesenteric afferent recordings were obtained from anaesthetized wild-type and CB2−/− mice using conventional extracellular recording techniques. Control responses to BK were obtained in all experiments prior to administration of either CB2 receptor agonist AM1241, or AM1241 plus the CB2 receptor antagonist AM630. Bradykinin consistently evoked activation of mesenteric afferents (n = 32). AM1241 inhibited the BK response in a dose dependent manner. In the presence of AM630 (10 mg kg−1), however, AM1241 (10 mg kg−1) had no significant effect on the BK response. Moreover, AM1241 had also no significant effect on the BK response in CB2−/− mice. Activation of the CB2 receptor inhibits the BK response in mesenteric afferents, demonstrating that the CB2 receptor is an important regulator of neuroimmune function. This may be a mechanism of action for the antinociceptive and antihypersensitive effects of CB2 receptor agonists.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Cannabinoid 2 (CB2) receptors are predominantly expressed peripherally, on a variety of immune tissues1 and hence are of particular interest as they offer the greatest possibility of a therapeutic target without psychoactive properties.2 There is good evidence that stimulation of the CB2 receptor can indeed have analgesic effects in various models, whilst having no apparent central nervous system effects.3,4 The first study to suggest the CB2 receptor as an analgesic target was by Calignano et al.,5 which was soon confirmed by a study showing that the CB2 receptor agonist AM1241 was antinociceptive in thermal hindpaw withdrawal tests in rats.6 This study has recently been repeated in mice and confirmed by AM1241’s lack of antinociceptive effects in CB2−/− mice.7 These studies were extended to demonstrate that AM1241 also reversed hypersensitivity in neuropathic pain states.8 AM1241 was also shown to be effective at inhibiting inflammatory hyperalgesia in a rat model using hindpaw injection of either carrageenan or capsaicin.9,10 Furthermore, a rat hindpaw incision model has also been used to demonstrate CB2 receptor mediated analgesia with three different CB2 receptor agonists; AM1241, GW405833 and HU-308.11

Cannabinoid 2 receptor mediated analgesia has been shown to involve inhibition of peripheral nerve firing. The majority of the studies to date have investigated the role of CB2 receptor activation in spinal sensory pathways. Nackley et al.12 used the neural activation marker c-fos to demonstrate that AM1241 inhibited c-fos protein expression in the spinal dorsal horn in response to hindpaw carrageenan injection. In a separate study, transcutaneous electrical stimulation of spinal wide dynamic range neurons was inhibited by AM1241 administration either locally in the hindpaw or intravenously, both in the presence and absence of peripheral carrageenan inflammation.13 Sagar et al.14 have recently reported that the CB2 receptor plays a functional role on dorsal root ganglia (DRG) neurons in neuropathic rats. Changes in intracellular calcium levels were recorded in response to capsaicin application in DRGs from sham and neuropathic rats and these responses were inhibited by the CB2 receptor agonist JWH-133. However, in in vivo experiments, spinal administration of JWH-133 attenuated mechanically evoked responses of spinal neurons in neuropathic, but not sham-operated rats. To date, there is only one study on the vagus, which indicates that CB2 receptor activation can inhibit firing of afferent vagal nerves.15 Nerve depolarizations were recorded from isolated vagal nerve preparations from guinea pig and human tissues in vitro in response to capsaicin, hypertonic saline and PGE2. The CB2 receptor agonist JWH-133 inhibited vagal afferent responses to these stimuli in a dose-dependent manner in both guinea pig and human preparations.

There are no studies that have investigated the effects of CB2 receptor activation in other non-somatic sensory nerve preparations, and hence it is not clear whether CB2 receptor agonists have similar inhibitory effects on visceral afferent nerve activation. In the current study, extracellular nerve recordings were made from mesenteric sensory nerves supplying the jejunum in naïve and CB2−/− mice. The aim of this study was to investigate whether CB2 receptor activation modulates visceral afferent responses to the immunogenic agent bradykinin (BK).

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Animals

Experiments were conducted using naïve C57BL6J mice (Charles River, QC, Canada) and CB2 receptor knockout mice (CB2−/−). CB2−/− mice (provided by Dr Andreas Zimmer) were generated in a C57BL6J background as described earlier.16 All mice were allowed free access to both regular solid food and water. All protocols and surgical procedures were approved by an independent Institutional Animal Care and Use Committee, in accordance with the guidelines of the Canadian Association for Laboratory Animal Science.

Drugs

Ketamine, xylazine and acepromazine were obtained from CDMV, (St Hyacinthe, QC, Canada). Bradykinin was obtained from Sigma (Oakville, ON, Canada) and dissolved in 0.9% phosphate buffered saline containing 1% bovine serum albumin. AM1241 (synthesized by Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium) and AM630 (Tocris Bioscience, Ellisville, MO, USA) were dissolved in a 20%β-cyclodextrin (β-CD; Sigma) solution.

Non-recovery surgical procedures

Procedures for in vivo extracellular electrophysiological recording that have previously been described in the rat17 were adjusted for application in the mouse. General anaesthesia was induced with an intraperitoneal injection of ketamine, xylazine and acepromazine (80, 50 and 1 mg kg−1 respectively) and was sustained by intravenous (i.v.) infusion of ketamine at 0.7–1.4 mg kg−1 min−1. The right external jugular vein was cannulated to allow maintenance anaesthesia and the left external jugular vein was cannulated for systemic administration of drugs. Body temperature was monitored with a rectal thermometer and maintained at around 37 °C by means of a heating blanket. A midline laparotomy was performed and the caecum was excised. A 5 cm loop of proximal jejunum was isolated and cannulated to act as an anchor to enable easier nerve dissection. The abdominal incision was sutured to a 20 mm-diameter steel ring to form a well that was subsequently filled with prewarmed (37 °C) light liquid paraffin.

Nerve preparation and afferent recording

A mesenteric arcade was placed on a black Perspex platform and a single nerve bundle was dissected from the surrounding tissue. This was severed distal from the wall of the jejunum (∼5–10 mm) to eliminate efferent nerve activity. It was then attached to one of a pair of platinum electrodes, with a strand of connective tissue wrapped around the other to act as a differential. The electrodes were connected to a 1902 amplifier [Cambridge Electronic Design (CED), Cambridge, UK], filtered and differentially amplified with the resulting signal digitized via a 1401 plus interface (CED) and captured on a PC using Spike2 software (CED).

Experimental protocols

In pilot experiments, a protocol was developed for repeated administration of BK at a dose that was consistently effective. Various doses were tested (from 0.1 to 10 μg kg−1) at different interval (from 5 to 20 min). In these experiments, the optimal conditions to elicit a prominent but repeatable afferent nerve response to BK were determined to be an i.v. bolus of BK at 3 μg kg−1 at 10-min intervals: this evoked a consistent response with no apparent desensitization within a 90 min period. At the beginning of each experiment, two control doses of BK were administered prior to administration of a CB2 receptor agonist ± CB2 receptor antagonist. At 1 min prior to the third administration of BK, the CB2 receptor agonist AM1241 was administered i.v. The BK response in the presence of AM1241 was recorded and compared with control BK responses. Subsequent doses of BK were given to determine the timecourse of AM1241’s actions. In the majority of experiments only one dose of AM1241 was tested, but in six experiments >1 dose was tested. A dose response curve of the effect of AM1241 (1–40 mg kg−1) on the BK response was performed in naïve C57BL6J mice (n = 25). From these experiments, an optimal dose of the CB2 receptor agonist AM1241 of 10 mg kg−1 was titred (50% inhibition of response) and used in the remaining experiments. The effect of 10 mg kg−1 AM1241 was tested in the presence of the CB2 receptor antagonist AM630 (10 mg kg−1 administered i.v. 1 min prior to AM1241 administration, n = 7). Furthermore, the effect of 10 mg kg−1 AM1241 was tested on the BK response in CB2−/− mice (n = 6) using the same protocol as detailed above.

Analysis of data

A nerve activity histogram was generated in real time using Spike2 by setting a threshold that distinguished between noise and action potential firing. This enabled the afferent nerve activity to be measured over time (shown in 5 s bins) in response to drug application. In calculations of % of the control BK response, the peak nerve activity after each BK administration was subtracted from the mean baseline activity (30 s prior to BK administration). Each BK response in the presence of the CB2 receptor agonist AM1241 was then expressed as a percentage of the control BK response. In all other bar graphs, the mean afferent firing rate in the 20 s prior to BK administration was subtracted from the mean afferent firing rate in the period 10–30 s after BK administration. Data are presented as the arithmetic mean ± SEM. Numbers of experiments in brackets represent the number of nerves recorded from (only one nerve recorded from per animal). Significant differences between group means were determined by appropriate use of Student's paired or unpaired t-test, Kruskal–Wallis test with Dunn's multiple comparison test, one- or two-way anova with postanalysis. A probability of P < 0.05 was considered to be indicative of a statistically significant difference.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Bradykinin (3 μg kg−1) consistently evoked an activation of mesenteric afferent nerves (Fig. 1A) in all experiments. This same dose of BK was used in all experiments to compare the effect of a CB2 receptor agonist ± a CB2 receptor antagonist on the BK response. The control response to BK was characterized by a rapid increase in afferent activity that peaked at 18 ± 2.8 s. At this time, point there was a peak increase in discharge over baseline of 26.2 ± 2.4 imp/s and a mean response duration of 93.2 ± 5.2 s (n = 32). The BK response was repeated every 10 min in pilot experiments and no desensitization was observed over time. An example of repeat administration of a control response to BK is shown in Fig. 1B and the mean data are illustrated in Fig. 1C.

image

Figure 1.  (A) An example afferent nerve recording of the response to i.v. injection of bradykinin (BK, 3 μg kg−1). (B) An example afferent nerve recording of the response to repeated application of BK (3 μg kg−1) at 10-min intervals. (C) The mean ± SEM (n = 9) increase in afferent nerve discharge in response to repeated BK (3 μg kg−1) administration. There was no significant difference in BK responses over time (one-way anovaP = 0.96).

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In further control experiments, the CB2 receptor agonist and antagonist solvent was tested in vehicle experiments. Repeated administration of 20 μL of a 20%β-CD solution had no effect on afferent nerve activity in three experiments tested (Fig. 2). However, administration of the CB2 receptor agonist AM1241 evoked a brief increase in afferent nerve activity in 13/20 experiments within 5 s of administration. The afferent nerve activity returned to baseline levels within 30 s. Bradykinin was administered 60 s after administration of the CB2 receptor agonist AM1241, at a time when the afferent nerve activity had returned to baseline levels. An example of the effects of a single dose of 10 mg kg−1 AM1241 on the BK response is illustrated in Fig. 3B in addition to an example of the effects of repeated application of the vehicle solution (20 μL of a 20%β-CD solution, Fig. 3A) on the BK response. The CB2 receptor agonist AM1241 had a comparative inhibitory effect on all phases of the BK response, but had no effect on the time course of activation as can be seen in the mean timecourse data for 10 mg kg−1 AM1241 in Fig. 4A. The inhibitory effect of AM1241 on the BK response was not long-lasting in these in vivo experiments. At a dose of 10 mg kg−1 AM1241, inhibition of the BK response changed from 50% inhibition (after 1 min) to 20% inhibition (after 15 min) when compared with the control BK response. The inhibitory effects of the CB2 receptor agonist AM1241 on the BK response were dose dependent, as shown in Fig. 4B.

image

Figure 2.  (A) An example afferent nerve recording of the response to i.v. injection of the vehicle solution (used for dissolving AM1241) and the CB2 receptor agonist AM1241 (10 mg kg−1): 20 μL of a 20%β-CD solution had no effect on afferent nerve activity whilst AM1241 evoked a brief increase in nerve firing. (B) Mean data (n = 3 for vehicle, n = 13 for AM1241) of the effect of 20%β-CD vehicle solution and AM1241 on afferent nerve activity. No significant differences in nerve activity were observed with the vehicle solution but in 13/20 AM1241 experiments there was a significant transient increase in nerve firing.

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image

Figure 3.  An example of the afferent nerve response to bradykinin (BK, [DOWNWARDS ARROW] = 3 μg kg−1 i.v.) prior to and after administration of (A) vehicle (20 μL of a 20%β-CD solution) and (B) AM1241 ([DOWNWARDS ARROW] = 10 mg kg−1 i.v.). The raw nerve recording is shown on the bottom of each trace and the nerve activity rate histogram is shown on top. A consistent BK response is observed in the absence of any other stimuli in both examples. However, following the vehicle there is no further change in the BK response, but the BK response is markedly attenuated after administration of the CB2 receptor agonist AM1241.

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image

Figure 4.  (A) Mean change in afferent activity in response to bradykinin (BK) in control conditions and in the presence of the CB2 receptor agonist AM1241 (10 mg kg−1, n = 9). The dotted line indicates those values that are significantly different from each other (values 15–45 s post-BK, P < 0.05). (B) A dose response graph showing the % of the peak control BK response in the presence of 1 mg kg−1 (n = 6), 5 mg kg−1 (n = 7), 10 mg kg−1 (n = 10) and 40 mg kg−1 (n = 3) AM1241. A Kruskal–Wallis test showed there was a significant effect of AM1241 overall on the afferent BK response (P < 0.001), with a significant decrease at 10 and 40 mg kg−1 (P < 0.05).

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The CB2 receptor antagonist AM630 completely abolished the effects of the CB2 receptor agonist AM1241 on the BK response (Fig. 5A,B). Bradykinin responses in the presence of both AM1241 and AM630 exhibited no apparent alteration in either the amplitude or the time course of the BK response. However, as AM630 has also been reported to behave as a weak inverse agonist at CB1,18 the effect of AM1241 on the BK response was also tested in CB2−/− mice. The CB2 receptor agonist AM1241 had no effect on the BK response in CB2−/− mice compared with the preceding control BK response (Fig. 5C,D). There was no significant difference in the control BK response between wild type and CB2−/− mice as is illustrated in Fig. 5A,C.

image

Figure 5.  (A) A timecourse graph showing the mean change in afferent activity in response to bradykinin (BK) in control conditions, in the presence of the CB2 receptor agonist AM1241 and in conjunction with the CB2 receptor antagonist AM630 (n = 7) in naïve mice (P < 0.05). (B) The mean increase in nerve firing in response to BK in control conditions, following administration of the CB2 receptor agonist AM1241 and in the presence of both AM1241 and AM630. One-way anova analysis indicates a significant difference between these groups (P < 0.05) and a Tukeys post-test shows a significant difference between BK and AM1241 (*P < 0.05). (C) A timecourse graph showing the lack of effect of AM1241 in CB2−/− mice (n = 6) is illustrated by the consistent mean BK response in control conditions and in the presence of AM1241. (D) The mean increase in response to BK ± AM1241 in CB2−/− mice. There was no significant inhibition of the BK response after AM1241 administration in CB2−/− mice (P = 0.8).

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

The results of this study demonstrate that the CB2 receptor agonist AM1241 inhibits the BK response of murine mesenteric afferent nerves. The effect of AM1241 on the BK response is demonstrably due to activation of the CB2 receptor as AM1241’s effects can be blocked by the CB2 receptor antagonist AM630 in C57BLJ6 mice, and as no effect of AM1241 was observed in CB2−/− mice.

The analgesic effects of CB2 receptor agonism have been well-described in somatic nerve pathways. This is the first report, however, that demonstrates that the CB2 receptor mediated inhibition of peripheral nerve firing also occurs in visceral nerve pathways; more specifically, visceral nerves supplying the intestinal tract. In somatic models, CB2 receptor agonism has been shown to be effective both as an analgesic under normal conditions6,7 and furthermore, to reverse hypersensitivity in a variety of inflammatory and hyperalgesic models.8–10

Administration of the CB2 receptor agonist AM1241 evoked a transient activation of mesenteric afferent nerves in 13/20 nerves tested. The timecourse of this response was approximately 5 s, which is consistent with a direct activation of the afferent nerve terminal. This direct response of AM1241 was not a vehicle artifact as a similar response to the AM1241 solvent alone was never observed. Moreover, as the mesenteric nerves being recorded from are a mixed population expressing a variety of different receptors, a direct response to AM1241 in only a subpopulation of nerves is consistent with a receptor mediated event. The receptor responsible for this transient activation was not investigated. However, this transient activation by AM1241 was still observed in CB2−/− mice (but not the BK inhibition) and so it does not appear to be mediated by CB2 receptors. Cannabinoid 1 receptors are potential candidates as they are expressed on both nodose19 and DRG neurons,20 but CB1 receptors have been reported to have inhibitory actions on neurons14,21,22 and it is therefore improbable that they are involved in mediating this direct excitatory response. Hence, the receptor responsible for this transient direct nerve activation remains to be elucidated.

Due to this direct nerve activation observed in some experiments with AM1241 administration, BK was always administered 1 min after AM1241 was applied. Hence, it is impossible to use the timecourse of AM1241’s inhibitory effect on the afferent nerve response to BK (∼1 min) to indicate whether this was a peripheral or central effect. Cannabinoid 2 receptors have recently been found to be expressed centrally,23 and a role for these receptors cannot be ruled out from these in vivo studies. However, given the predominant peripheral expression of CB2 receptors24 and as a similar inhibitory action of the CB2 receptor has been reported in an in vitro vagus preparation,15 it is unlikely that any of AM1241’s observed effects are mediated by the central nervous system.

In these experiments, several doses of BK were administered during the course of each experiment. Several control experiments were performed to evaluate the consistency of the BK response with time and with vehicle administration. The afferent nerve response to BK remained consistent throughout the course of these control studies. Any unstable recordings where there was a clear and significant increase or decrease in spontaneous nerve activity over time were not analysed for this study. The inhibition of the BK response by AM1241 typically lasted for a maximum of 30 min before the nerve response to BK was returned to control levels. These transient inhibitory effects are consistent with either CB2 receptor desensitization and/or the degradation of AM1241, but further experiments are required to determine the cause of these transient effects.

The inhibitory effect of the CB2 receptor agonist AM1241 on the afferent BK response was not observed in the presence of the CB2 receptor antagonist AM630. This suggests that AM1241’s inhibitory effects are mediated by CB2 receptors. However as AM630 has also been reported to be a weak inverse CB1 agonist, and it is possible that AM630 could also be acting as a functional antagonist, these experiments alone are not conclusive. Hence, further experiments were performed on CB2−/− mice to determine if inhibitory effects of AM1241 were recorded. There was no significant difference in the control responses to BK between wild type and CB2−/− mice. However, as no inhibition of the BK response was found with the CB2 receptor agonist in CB2−/− mice, together with the AM630 data in wild type animals, it is concluded that AM1241’s inhibitory actions are mediated by receptor CB2.

This CB2 receptor mediated inhibition of normal responses to the neuroimmunogenic agent BK, is consistent with an antinociceptive action of the CB2 receptor on intestinal sensory neurons.25 Both CB2 and CB1 receptors have been reported to inhibit experimental colitis induced by mustard oil26 demonstrating that both receptors may have protective effects mediated directly or indirectly by intestinal sensory neurons. However, the focus of this study was CB2 receptor's effects on the BK response. The response of mesenteric afferents to BK is known to be a peripherally and not centrally mediated effect as the activation is within approximately 5 s and is similar in in vitro preparations.27 Bradykinin is a pro-inflammatory agent which activates a number of pathways that can themselves have direct and indirect nerve responses. Bradykinin mediates its effects via two G protein-coupled receptors, B1 and B2: expression of the B1 receptor is primarily induced by inflammatory challenge, whereas, the B2 receptor is constitutively expressed. Bradykinin has been shown to directly activate afferents through B2 receptor activation28,29 and has been shown to be present on both DRG30,31 and nodose neurons.32 However, it has also been demonstrated that BK has indirect effects on intestinal afferents. It was hypothesized by Maubach and Grundy28 that in intestinal afferents in the rat in vitro the response to BK activated a self-sensitizing pathway involving prostaglandin activation. As prostaglandins are key mediators of immune cell function, it is speculated that activation of the CB2 receptor on immune cells inhibits the immune cascade stimulated by BK, and hence blocks the overall magnitude of the BK response. There is evidence that B2 receptors can be upregulated by nerve injury, which may make the role of the CB2 receptor even more important in injury and/or inflammatory conditions: an increase in B2 receptor expression in DRG neurons has been observed in a variety of somatic nerve injury models,33–35 where upregulation is dependent on nerve growth factor (NGF) and glial derived neurotrophic factor (GDNF),36 and NGF also causes an acute increase in BK sensitivity.37

The inhibition of the BK response by CB2 receptor activation could be due to two different mechanisms: a direct effect of AM1241 on afferent nerve terminals; and/or an indirect effect mediated by a non-neuronal cell. Given the tissue distribution of CB2 receptors under normal conditions24 and the activation of an immune pathway by BK,28 it is likely that CB2 receptors expressed on immune cells play a significant role in these inhibitory effects. The expression of the CB2 receptor on mast cells was first demonstrated by Facci et al.38 Studies in our laboratory were performed to test the effects of AM1241 on cultured RBL-2H3 cells, a rat mucosal-type mast cell line. The CB2 receptor agonist AM1241 inhibited the response of these cells to ionomycin, indicating that these cells express functional CB2 receptor (data not shown). These preliminary findings are consistent with a role of mast cells in the in vivo actions of AM1241 on nerve activity. However, there is no direct evidence that the peripheral actions of AM1241 recorded in the present study involve mast cells.

The activation of CB2 receptor on immune cells may be an important mechanism for the regulation of a variety of intestinal functions, particularly in response to an inflammatory challenge. CB 2 receptor activation has been shown to restore normal intestinal transit in lipopolysaccharide (LPS)-treated rats,39 but has no effect in naïve rats.39,40 This inhibition in transit time was observed within 90 min of LPS treatment, suggesting that CB2 receptor expression is rapidly activated by the inflammation. Consistent with this observation, expression of CB2 receptor has been shown to be induced by LPS and other inflammatory challenges in rat peritoneal macrophages, but are not detectable in naïve macrophages.41 It remains to be seen whether CB2 receptor agonism could also reverse inflammatory hypersensitivity in afferents supplying the intestinal tract.

A recent study has demonstrated that a similar postinflammatory increase in CB2 receptor expression also occurs in human intestine.42 CB 2 receptor expression was assessed in both normal and inflammatory bowel disease (IBD) colonic tissue. In sections of normal colon, CB2 receptor expression was observed primarily in macrophages and to a lesser extent on plasma cells in the lamina propria. However, in colon from IBD patients, CB2 receptor expression was also observed in the colonic epithelia. The epithelial CB2 receptor expression was also observed in patients with Crohn's disease in this study. Hence, there is an upregulation of CB2 receptor in inflammatory conditions within the intestinal tract. This may reflect an intrinsic intestinal mechanism by which endocannabinoids activate the CB2 receptor to counteract inflammatory challenges.

As the CB2 receptor is upregulated in inflammatory bowel conditions,42 CB2 receptor agonists normalize increased intestinal transit following an inflammatory insult,39 and CB2 receptor agonists inhibit afferent nerve responses to the neuroimmunogenic agent BK, CB2 receptor agonists have promising therapeutic potential in the management of a variety of intestinal disorders. The precise mechanism by which the CB2 receptor produces its various effects remains to be elucidated. As speculated above, the anti-inflammatory effect of the CB2 receptor on immune cells may be the critical mode of action of the CB2 receptor, to act as a brake on the release of pro-inflammatory mediators from macrophages and mast cells. This in turn leads to the antinociceptive effects of CB2 receptor agonists, although the possibility of an additional direct effect on nerve terminals cannot be ruled out. Hence, activation of the CB2 receptor on immune components such as mast cells, either by endocannabinoids or by administration of CB2 receptor agonists, could attenuate a variety of different immune-modulated pathways to normalize intestinal transit and afferent hypersensitivity.

In summary, CB2 receptor activation has been shown in this study to inhibit afferent nerve responses to BK. It is likely that CB2 receptor agonists alter mesenteric afferent nerve activity by both direct and indirect effects on nerve terminals. It would be of interest to determine whether CB2 receptor agonism could reverse a model of inflammatory hypersensitivity in afferents supplying the intestinal tract. As there is evidence to suggest that CB2 receptor in the intestine can be upregulated, CB2 receptor agonists in inflammatory and immune-related conditions may be beneficial therapeutic compounds.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
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