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J Dent Res 82(4): 308-311, 2003
© 2003 International and American Associations for Dental Research

RESEARCH REPORT
Biological

ß2-Adrenoceptor Regulation of CGRP Release from Capsaicin-sensitive Neurons

W.R. Bowles1, C.M. Flores2, D.L. Jackson3, and K.M. Hargreaves2,*

1 Division of Endodontics, University of Minnesota School of Dentistry;
2 Department of Endodontics, UTHSCSA School of Dentistry, Mail Code 7892, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900; and
3 Department of Oral Medicine, University of Washington School of Dentistry;

*corresponding author, Hargreaves{at}UTHSCSA.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Previous studies have suggested that neurotransmitter substances from the sympatho-adrenomedullary system regulate pulpal blood flow (PBF), in part, by the inhibition of vasoactive neuropeptide release from pulpal sensory neurons. However, no study has evaluated the role of ß-adrenoceptors. We evaluated the hypothesis that activation of ß-adrenoceptors inhibits immunoreactive calcitonin gene-related peptide (iCGRP) release from capsaicin-sensitive nociceptive neurons via in vitro superfusion of bovine dental pulp. Either norepinephrine or epinephrine inhibited capsaicin-evoked iCGRP. The norepinephrine effect was blocked by the selective ß2-adrenoceptor antagonist, ICI 118,551, but not by pre-treatment with the selective ß1-adrenoceptor antagonist, atenolol. In addition, application of albuterol, a selective ß2-adrenoceptor agonist, significantly blocked capsaicin-evoked release of iCGRP. Collectively, these studies demonstrate that activation of ß2-adrenoceptors in dental pulp significantly reduces exocytosis of neuropeptides from capsaicin-sensitive nociceptors. This effect may have physiologic significance in regulating PBF. Moreover, since capsaicin selectively activates nociceptors, ß2-adrenoceptor agonists may have clinical utility as peripherally acting therapeutics for dental pain and inflammation.

KEY WORDS: dental pulp • superfusion • CGRP • capsaicin • norepinephrine • albuterol • ICI 118 • 551 • atenolol • epinephrine


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The sympatho-adrenomedullary system plays a key role in regulating vascular homeostasis. The two major catecholamines of this system, norepinephrine and epinephrine, produce their effects via activation of {alpha}- and ß-adrenoceptors. Dental pulp tissue expresses both {alpha}- and ß-adrenoceptors and, thus, is responsive to catecholamine administration (Tønder and Naess, 1978; Okabe et al., 1989; Liu et al., 1990; for review, see Suda and Ikeda, 2002).

Previous studies have demonstrated that post-ganglionic sympathetic fibers and capsaicin-sensitive trigeminal afferent fibers have opposing effects on pulpal blood flow (PBF) in several species (Tønder and Naess, 1978; Kim and Dörscher-Kim, 1990; Olgart, 1992; Andrew and Matthews, 1996; Kim et al., 1996; Berggreen and Heyeraas, 2000). In addition, results from whole-animal studies measuring vascular parameters of PBF have led to the hypothesis that sympathetic fibers act in part by inhibition of capsaicin-sensitive trigeminal peptidergic afferent fibers (Kerezoudis et al., 1993a,b). Studies on cultured dorsal root ganglion neurons indicate that certain small-diameter sensory neurons may express the ß-adrenoceptor (Khasar et al., 1999). However, to date, no study has directly tested whether activation of ß-adrenergic receptors inhibits neuropeptide release from certain peptidergic sensory neurons innervating dental pulp.

In this study, using release of iCGRP from isolated superfused bovine dental pulp slices as a dependent measure, we used a biochemical approach to determine whether activation of ß-adrenergic receptors by exogenous adrenergic agonists inhibits exocytosis from trigeminal peptidergic afferent neurons. CGRP in dental pulp originates from trigeminal sensory neurons and thus represents a selective marker of certain peptidergic sensory neurons (Wakisaka et al., 1987), and the use of capsaicin as the test stimulus selectively targets the nociceptive subset thereof. In this report, we provide evidence that activation of ß2-adrenoceptor exogenous adrenergic agonists, but not ß1-adrenoceptors, inhibits capsaicin-evoked exocytosis of iCGRP from isolated neuronal terminals in bovine dental pulp.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The superfusion method was used as previously described (Hargreaves et al., 1992). In brief, bovine mandibular incisor teeth (from 2- to 4-year old Holstein cows) were collected at a local slaughterhouse and rapidly transported on ice to the laboratory. A McIlwain tissue chopper (Mickle Lab. Eng. Co. Ltd., Gomshall, Surrey, England) was used to prepare 200-µm2 slices of tissue, and ~ 250-mg aliquots were superfused with oxygenated Krebs’ buffer (420 µL/min, 37°C).

Samples were collected over seven-minute periods after a 60-minute wash-out period. All chemicals and test drugs were purchased from Sigma Chemical Co. (St. Louis, MO, USA). Levels of iCGRP were measured by radioimmunoassay with an immunomagnetic separation method as previously described (Richardson et al., 1998). Separate standard curves were prepared with all test drugs to verify lack of interference with the assay. The minimum detection limit was 1-3 fmol/tube.

The data were analyzed by one-way ANOVA followed by Duncan’s multiple-range test for determination of differences between groups. A Student’s t test was conducted when two groups were compared. A difference was accepted as significant if the probability that it occurred due to chance alone was less than 5% (p < 0.05). Release data were normalized by calculation of the % increase over baseline rates of iCGRP release according to the formula 100 x (peak release - baseline)/(baseline). This transformation reduced intra-experimental variability due to differences among animals. Data are presented as mean + SEM.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The activation of capsaicin-sensitive peptidergic fibers produced an approximately two- to three-fold increase in iCGRP release from terminals in the isolated superfused dental pulp (Fig. 1Go). In terms of absolute rates of release, capsaicin (10 µM) increased iCGRP levels released into the superfusate from 17.8 + 4 fmol/G/7 min to 63.4 + 3.7 fmol/G/7 min (p < 0.01). Pre-treatment with epinephrine (p < 0.01) or with norepinephrine (p < 0.05) at concentrations of 10 nM significantly inhibited capsaicin-evoked release of iCGRP (p < 0.05), with epinephrine producing a greater inhibition than norepinephrine (p < 0.01)



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  		Figure 1. Effect of pre-treatment with vehicle, norepinephrine (10 nM), or epinephrine (10 nM) on capsaicin-evoked release of immunoreactive calcitonin gene-related peptide (iCGRP) from in vitro-superfused dental pulp. Bovine dental pulp was collected, sectioned into 200-µm2 slices, and superfused with oxygenated Krebs’ buffer. Levels of iCGRP released from dental pulp were collected over seven-minute fractions and measured by radioimmunoassay. The test agents or vehicle was administered from 0-28 min, and capsaicin (10 µM) was administered to all tissues over 21-28 min. Data are calculated as % increase over basal rate of release. Error bars are SEM. **p < 0.01 vs. vehicle. {dagger} p < 0.01 vs. vehicle and norepinephrine.

 
The next experiment determined whether the inhibitory effect of norepinephrine could be mediated in part by a ß-adrenergic receptor mechanism (Fig. 2Go). To evaluate this hypothesis, we pre-treated separate groups of tissue with a test drug (vehicle or 100 nM of either a ß1 or a ß2 receptor antagonist) for 7 min, and then received a combination of the test drug + norepinephrine (10 nM) for 7 min, followed by application of a combination of test drug + norepinephrine (10 nM) + capsaicin (10 µM) for 7 min. Administration of the selective ß1-antagonist atenolol (Parker et al., 1998; Todorov et al., 2001) had no effect on norepinephrine inhibition of capsaicin-induced exocytosis. Conversely, pre-treatment of the tissue with the selective ß2 antagonist ICI 118,551 (Todorov et al., 2001; Heubach et al., 2002) completely blocked the norepinephrine inhibition of capsaicin-induced exocytosis (p < 0.01).



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  		Figure 2. Effect of pre-treatment with a ß1-antagonist (atenolol), a ß2-antagonist (ICI 118,551), or vehicle on norepinephrine (10 nM) inhibition of capsaicin-evoked release of iCGRP from bovine dental pulp. The ß-adrenoceptor antagonists (both at 100 nM) or vehicle was pre-treated for 7 min prior to application of norepinephrine (10 nM) or vehicle for an additional 7 min. All groups were then stimulated with capsaicin (10 µM) for 7 min. ** p < 0.01 vs. vehicle and ICI 118,551 groups. Error bars are SEM. N = 6-8/group.

 
To confirm that activation of pulpal ß2-adrenoceptors inhibits neuropeptide exocytosis from peripheral terminals of capsaicin-sensitive peptidergic afferent fibers, we next evaluated whether albuterol, a selective ß2 agonist (Nichol et al., 1990; Brochet et al., 1996), was capable of reducing capsaicin-evoked iCGRP release (Fig. 3Go). As compared with tissue treated with vehicle, tissue treated with albuterol (10 µM) exhibited a significantly reduced capsaicin-evoked iCGRP release (p < 0.01).



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  		Figure 3. Effect of pre-treatment with vehicle or a ß2-adrenoceptor agonist (albuterol, 10 µM) on capsaicin (10 µM)-evoked release of immunoreactive calcitonin gene-related peptide (iCGRP) from in vitro-superfused dental pulp. Levels of iCGRP were measured as described in the legend to Fig. 1Go. Data are calculated as % increase over basal rate of release. Error bars are SEM. **p < 0.01 vs. vehicle.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study evaluated the hypothesis that activation of ß-adrenoceptors by exogenous adrenergic agonists inhibits capsaicin-evoked exocytosis of iCGRP from isolated peptidergic afferent terminals innervating bovine dental pulp. At the 10-nM concentration evaluated, epinephrine was more effective than norepinephrine in inhibiting capsaicin-evoked iCGRP release. In terms of potency, epinephrine is more potent than norepinephrine for stimulating ß2-adrenoceptors and is approximately equal to norepinephrine for stimulating {alpha}1-, {alpha}2-, and ß1-adrenoceptors (Hoffman et al., 1996); therefore, we first considered that this catecholamine-mediated inhibitory effect could be due, at least in part, to the stimulation of ß2-adrenoceptors. This hypothesis was confirmed when we demonstrated that the norepinephrine effect could be significantly reduced by pre-treatment with ICI 118,551 (a selective ß2-adrenoceptor antagonist), but not by pre-treatment with atenolol (a selective ß1-adrenoceptor antagonist). Moreover, the administration of albuterol, a selective ß2-adrenoceptor agonist, significantly blocked capsaicin-evoked release of iCGRP. Collectively, these studies demonstrate that, in dental pulp, activation of ß2-adrenoceptors, but not ß1-adrenoceptors, is significantly able to reduce exocytosis of neuropeptides from capsaicin-sensitive nociceptors innervating this tissue.

Although the biochemical method used in this study is useful for characterizing pharmacological mechanisms of action, it is not suitable for identifying the cell type that expresses the ß2-adrenoceptor mediating this response. At least two hypotheses can be advanced for the cell type expressing the ß2-adrenoceptor. First, the ß-adrenoceptor could be expressed on pulpal sympathetic fibers, where its activation could lead to enhanced release of endogenous norepinephrine or other neurotransmitter substances (Lundberg et al., 1990) that could then have a direct inhibitory action on sensory terminals. We view this possibility as unlikely, since the inhibitory effect observed after application of exogenous norepinephrine was blocked by pre-treatment with a ß2-adrenoceptor antagonist, a result not predicted by this hypothesis. Second, it is possible that this ß2-mediated inhibitory effect is due to activation of ß2-adrenoceptors expressed by capsaicin-sensitive trigeminal peptidergic neurons that innervate dental pulp, which likely express the vanilloid receptor type 1 (VR1), a receptor activated by capsaicin (Caterina et al., 1997). Thus, we hypothesize that capsaicin-sensitive trigeminal neurons innervating dental pulp may express ß2-adrenoceptors. To our knowledge, no study has yet evaluated this hypothesis. However, it has been reported that norepinephrine actives ß-adrenoceptors expressed in normal (uninjured) small-diameter sensory neurons, many of which are known to express the VR1 receptor (Abdulla and Smith, 1997; Caterina et al., 1997). In addition, neonatal capsaicin treatment, a procedure that destroys capsaicin-sensitive fibers, also reduced ß-adrenoceptor binding sites in the spinal cord (Patterson and Hanley 1987). Taken together, these data are consistent with the hypothesis that capsaicin-sensitive trigeminal afferent fibers express the ß2-adrenoceptor.

There are at least three implications from the present data. First, we have previously reported that activation of pulpal sympathetic fibers inhibits capsaicin-evoked release of neuropeptides from dental pulp (Hargreaves et al., 2003). This effect was predominantly due to activation of {alpha}-adrenoceptors, since approximately 80% of this sympathetic effect was blocked by application of {alpha}-adrenergic antagonists. We do not know if endogenous norepinephrine reaches sufficient concentrations to activate the ß2-adrenoceptors described in this present report. However, at least under the present experimental conditions, activation of ß2-adrenoceptors can account for only up to 20% of sympathetic fiber modulation of capsaicin-sensitive nociceptors.

Second, the demonstration of ß2-adrenoceptor regulation of iCGRP exocytosis may partially explain the prior observation that systemic administration of isoproterenol, a non-specific ß1/ß2-adrenoceptor agonist, evoked a biphasic effect on PBF (Tønder, 1976; Liu et al., 1990; Kim, 1985; Okabe et al., 1989). Thus, it is possible that the isoproterenol-mediated reduction in PBF could be due to inhibition of CGRP release from trigeminal peptidergic afferent fibers [as well as the previously advanced hypothesis of ’stealing’ of blood flow by adjacent tissues (Tønder, 1976)].

The third implication from the present study derives from the observation that capsaicin selectively activates a large subpopulation of nociceptors (Caterina et al., 1997; Caterina and Julius, 2001). If capsaicin-sensitive nociceptors express the ß2-adrenoceptor, then it is possible that ß2-adrenoceptor agonists may have clinical utility as peripherally acting therapeutics for dental pain and inflammation. In support of this hypothesis, most (Brochet et al., 1986; Nakamura and Lico, 1986; Nichol et al., 1990; Peng et al., 1992; Mico et al., 1997) but not all (Khasar et al., 1999) studies have reported that ß-adrenoceptor agonists, including albuterol, have significant antinociceptive and antihyperalgesic effects in various pain models. Although some of these effects are known to be centrally mediated, the present results are consistent with an additional peripheral site of ß2-adrenoceptor regulation via capsaicin-sensitive peptidergic nociceptive afferent fibers innervating dental pulp.


   ACKNOWLEDGMENTS
 
This research was supported by grants from NIDCR/NIH, DE12888 (KMH), F32DE05659, and DE00270 (for DLJ).

Received August 7, 2002; Last revision November 21, 2002; Accepted January 16, 2003


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