Anesth Analg 2006;103:471-477
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000223680.54063.f6
PAIN MEDICINE
The Contribution of Alpha-1 and Alpha-2 Adrenoceptors in Peripheral Imidazoline and Adrenoceptor Agonist-Induced Nociception
Ahmet Dogrul, MD,
lke Coskun, and
Tayfun Uzbay
From the Gülhane Military Medical Academy, Faculty of Medicine, Department of Medical Pharmacology, Psychopharmacology Research Unit, Ankara, Turkey.
Address correspondence and reprint requests to Ahmet Dogrul, MD, Gülhane Military Medical Academy, Faculty of Medicine, Department of Medical Pharmacology, Ankara, Turkey. Address e-mail to dogrula{at}gata.edu.tr.
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Abstract
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We evaluated the effects of activation of peripheral adrenoceptors (AR) and imidazoline receptors on nociception and the contribution of 
-1 and -2 AR receptors in agonist-induced nociception by using the tail-flick test in mice. Clonidine (-2 AR agonist), agmatine (imidazoline receptor and -2 AR agonist), noradrenaline (mixed -1 and -2 AR agonist), phenylephrine (-1 AR agonist), or 0.9% saline was given by intradermal injection (10 µL) into the tail. The intradermal injection of clonidine (1, 3, and 10 µg) and agmatine (3, 30, and 50 µg) produced dose-dependent antinociception, whereas noradrenaline (1, 10, and 30 µg) and phenylephrine (1, 10 and 30 µg) produced dose-dependent thermal hyperalgesia. Clonidine (10 µg) and agmatine (50 µg)-induced peripheral antinociception were antagonized by pretreatment with yohimbine (2.5 mg/kg IP), a selective -2 AR antagonist, but not by prazosin (1 mg/kg IP), a selective -1 AR antagonist. Noradrenaline (30 µg) and phenylephrine (30 µg)-induced thermal hyperalgesia were antagonized by prazosin (1 mg/kg IP) but not by yohimbine (2.5 mg/kg IP). Our results suggest that local thermal hyperalgesic effects of noradrenaline and phenylephrine are linked to -1 AR and the peripheral antinociceptive action of clonidine and agmatine are linked to -2 AR.
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Introduction
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Noradrenaline (NE), a principal neurotransmitter in the sympathetic nervous system, is involved in various body functions, including nociception (1–3). NE is the endogenous ligand for both - and ß-adrenergic receptor (AR). It is generally accepted that the AR plays an important role in the modulation of nociception by the sympathetic nervous system (2). However, there is some controversy regarding the roles of each of the AR subtypes, -1 and -2, in nociception (2–4). The spinal administration of NE, a mixed -1 and -2 AR agonist, or of phenylephrine, an -1 receptor agonist, has been reported to produce antinociception (3,5). However, other studies showed that intradermal injection of NE and phenylephrine produced pain and hyperalgesia (6,7). Thus, NE and phenylephrine can be either pronociceptive or antinociceptive, depending on the site of delivery. On the other hand, either spinal or topical administration of clonidine, an -2 AR agonist, produced antinociception (8). However, there is evidence that several pharmacologic actions of -2 AR agonists are mediated via activation of not only -2 AR but also by imidazoline receptors (3). Agmatine has recently been found in various tissues and in the central nervous system, where it represents a novel neurotransmitter/neuromodulator (10,11). Many studies have shown that agmatine binds to both the imidazoline receptors and to the 2-AR (3,9,10).
After systemic administration, drugs can be distributed in peripheral, spinal, and supraspinal sites. The relative contribution of these different sites to the overall pharmacologic effect of a receptor agonist depends on several factors, such as the location of the relevant receptors, the site of administration (systemic, local-peripheral, or spinal), and redistribution from the site of drug administration. The neuronal pathways and architecture within spinal and supraspinal sites are very complex, making it difficult to elucidate the role of individual subtypes of -adrenergic receptors in the modulation of nociception. The skin is innervated with sensory nerve terminals and has cutaneous nociceptors responsive to heat in the superficial layers of the epidermis (11). Sympathetic postganglionic efferents are involved in the modulation of nociceptive transmission in the periphery (2). The localized peripheral administration of drugs allows a larger local concentration of drug at the site of injection, while leading to a smaller systemic concentration compared with systemic administration (12). Thus, local injection of AR agonist into the skin allows one to reconcile contradictory data in the pronociceptive or antinociceptive effects of AR agonists. AR are expressed by many other peripheral cell types, including peripheral sensory neurons (1,13). However, the expression of imidazoline receptors in peripheral sensory neurons remains to be clarified. The peripheral effects of imidazoline agonist on nociception have not yet been identified.
We conducted this study to determine whether the activation of peripheral adrenergic and imidazoline receptors produce antinociceptive and/or hyperalgesic effects and to define the contribution of -1 and -2 AR for their action in the peripheral sites.
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METHODS
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Adult male Balb/C mice (25–30 g) were used. They were placed in a quiet and temperature- and humidity-controlled room (22°C ± 2°C and 60% ± 5%, respectively) in which a 12 h:12 h light:dark cycle was maintained (8:00 am–08:00 pm light). The experiments were performed according to the rules of the Guide for the Care and Use of Laboratory Animals adopted by the National Institutes of Health and the Declaration of Helsinki. The study was approved by the Animal Care Ethics Committee of Gülhane Academy of Medicine.
Clonidine, agmatine, NE, phenylephrine, prazosin, and yohimbine were obtained from Sigma (St. Louis, MO). All drugs were freshly dissolved in 0.9% sterile saline except prazosin. Prazosin was dissolved in heated distilled water. The drug or 0.9% sterile saline was injected intradermally in the tail with 30-gauge needle and in a volume of 10 µL. To determine whether the AR subtype is involved in antinociception or hyperalgesia, the selective -1 AR antagonist prazosin and the selective -2 antagonist yohimbine were given IP in a volume of 0.1 mL/10 g 20 min before peripheral drug or saline administration.
Antinociception and thermal hyperalgesia were assessed using the radiant heat tail-flick test (Columbus, OH; Type 812). The tails of the mice were marked with a pen 3 cm from the tip. The light beam was focused onto the tail both at the marked site and 1–2 cm proximal to the site to test for a localized effect of drug administration. Baseline (BL) tail-flick latency was determined for each mouse. Tail-flick latencies from the proximal site were similar to the BLs at the marketed sites. For the antinociceptive studies, the BL latencies ranged from 2.5 to 3.5 s, and a cut-off time of 8 s was used to prevent tissue damage. For thermal hyperalgesia studies, voltage to the light source was adjusted to yield BL latencies ranging 7–10 s, which allowed for the detection of increased nociceptive response. The drug or saline were injected subcutaneously with a 30-gauge needle on the marked site of the tail. After drug or saline (0.9%) administration, the test latencies (TL) were measured at an indicated time on drug-injected sites and at the proximal segment. For the antinociceptive studies, the data were expressed as %antinociception, which was calculated using the equation: %antinociception = ((TL – BL)/(8 – BL)) x 100. For thermal hyperalgesic effect, data were expressed as %change in tail-flick latencies = (TL – BL)/BL x 100. Each animal was used as its own control. All values were expressed as mean ± sem.
A nonparametric method of statistical analysis was used. Statistical significance was evaluated by Kruskal-Wallis test (P < 0.05), followed by Dunnett’s multiple test for individual comparisons (P < 0.05).
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RESULTS
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Peripheral Antinociceptive Action of Clonidine and Agmatine and the Effects of Prazosin and Yohimbine on the Antinociceptive Action of Clonidine and Agmatine
Mean baseline latencies for all treatment groups in antinociception studies ranged between 2.7 ± 0.19 and 2.4 ± 0.26 s. Saline (0.9%) administration did not alter BL responses in control animals during the experiments. However, intradermal local injection of clonidine (1, 3, and 10 µg) and agmatine (3, 30, and 50 µg) produced dose-dependent antinociception, as indicated by increased tail-flick latencies (Fig. 1A and Fig. 2A). The antinociceptive response was rapidly increased from BL to 72% antinociception at 10 min and peaked at 79% antinociception at 30 min after the largest dose of clonidine (10 µg) (Fig. 1A). After the largest dose of agmatine (50 µg), the antinociceptive response slowly increased to only 22% antinociception at 10 min and peaked at 67% antinociception at 30 min (Fig. 2A). No antinociceptive response was seen with clonidine (1 and 3 µg) (Fig. 1B) and agmatine (3, 30, and 50 µg) when the heat stimulus was applied to the proximal, uninjected site (Fig. 2B). However, clonidine at 10 µg produced an antinociceptive effect when heat was applied at the proximal site (Fig. 1B). In a separate group of animals, we compared the antinociceptive effects of clonidine (10 µg) and saline (0.9%) at drug-injected sites and nondrug-injected control sites. Saline (0.9%) did not alter BL responses significantly in saline noninjected control sites when compared with saline-injected sites during the experiments (Fig. 3). However, clonidine (10 µg) produced significant, but weaker, antinociceptive effects in drug noninjected control sites when compared with drug-injected sites (Fig. 3).
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Figure 1. Dose-dependent antinociceptive effects of local injection of clonidine. Groups of mice were injected with clonidine (1, 3, and 10 µg) intradermally into the tail and then tested in the tail-flick assay at the indicated time at the injection site (A) and a more proximal segment 1–2 cm from it that was a nondrug-injected site (B). Data are expressed as mean ± sem. n = 6–8 per group. *P < 0.05, significantly different from saline (0.9%).
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Figure 2. Dose-dependent antinociceptive effects of local injection of agmatine. Groups of mice were injected with agmatine (3, 30, and 50 µg) intradermally into the tail and then tested in the tail-flick assay at the indicated time at the injection site (A) and more proximal segment 1–2 cm from it that was a nondrug-injected control site (B) Data expressed as mean ± sem. n = 6–8 per group. *P < 0.05, significantly different from saline (0.9%).
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Figure 3. Groups of mice were injected with clonidine (10 µg) and saline intradermally into the tail and then tested in the tail-flick assay at the indicated time at the injection site and more proximal segment 1–2 cm from it that was a nondrug-injected control site. Data expressed as mean ± sem. n = 6–8 per group. *P < 0.05, significantly different from corresponding injected sites.
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Prazosin (1 mg/kg IP) or yohimbine (2.5 mg/kg IP) pretreatment alone did not change the BL latencies (data not shown). However, clonidine- (10 µg) and agmatine- (50 µg) induced peripheral antinociception was completely antagonized by yohimbine (2.5 mg/kg IP) but not by prazosin (1 mg/kg IP) pretreatment (Fig. 4A and Fig. 4B).
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Figure 4. The effects of prazosin and yohimbine on peripheral clonidine- (A) and agmatine- (B) induced antinociception. Groups of mice were pretreated with prazosin (1 mg/kg IP) and yohimbine (2.5 mg/kg IP) 30 min before local injection of clonidine (10 µg) (A) and agmatine (50 µg) (B) into the tail and tested in the tail-flick assay at the indicated time at the injection site. Data expressed as mean ± sem. n = 6–8 per group. *P < 0.05 significantly different from clonidine (10 µg) and agmatine (50 µg) alone.
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Thermal Hyperalgesia Induced by Peripheral Noradrenaline and Phenylephrine Injection and the Effects of Prazosin and Yohimbine on Thermal Hyperalgesic Action of Noradrenaline and Phenylephrine
Mean BL latencies for all treatment groups in the hyperalgesia studies ranged between 8.3 ± 0.94 and 9.2 ± 1.1 s. Intradermal injections of NE and phenylephrine (1, 10, and 30 µg) into the tail produced dose-dependent thermal hyperalgesia as indicated by decreased tail-flick latencies (Fig. 5A and 6A). The thermal hyperalgesic effect was evident at 5 min and lasted 30 min after the largest dose of NE and phenylephrine (30 µg) (Fig. 5A and 6A). No thermal hyperalgesic effect was seen with NE (1, 10, and 30 µg) (Fig. 5B) and phenylephrine (1, 10, and 30 µg) (Fig. 6B) when heat stimulus was applied proximal to the site of drug injection. Neither prazosin (1 mg/kg IP) nor yohimbine (2.5 mg/kg IP) produced any changes in the BL thermal threshold in control animals (data not shown). However, prazosin (1 mg/kg IP) completely antagonized the peripheral thermal hyperalgesic effects of NE and phenylephrine (30 µg) whereas yohimbine (2.5 mg/ kg IP) did not alter thermal hyperalgesia induced by NE and phenylephrine (30 µg) (Fig. 7A and 7B).
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Figure 5. Dose-dependent thermal hyperalgesic effects of noradrenaline. To show hyperalgesia more promptly, the voltage to the light source of tail-flick was decreased to yield baseline latencies ranging 7–10 s, which allowed for the detection of increased pain response. Groups of mice were injected with noradrenaline (1, 10, and 30 µg) intradermally into the tail and then tested in the tail-flick assay at the indicated time at the injection site (A) and a more proximal segment 1–2 cm from it that was a nondrug-injected control site (B). Data are expressed as mean ± sem. n = 6–8 per group. *P < 0.05, significantly different from saline (0.9%).
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Figure 6. Dose-dependent thermal hyperalgesic effects of phenylephrine. To show hyperalgesia more promptly, the voltage to the light source of tail-flick was decreased to yield baseline latencies ranging 7–10 s, which allowed for the detection of increased pain response. Groups of mice were injected with noradrenaline (1, 10, and 30 µg) intradermally into the tail and then tested in the tail-flick assay at the indicated time at the injection site (A) and a more proximal segment 1–2 cm from it that was a nondrug-injected site (B). Data are expressed as mean ± sem. n = 6–8 per group. *P < 0.05, significantly different from saline (0.9%).
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Figure 7. The effects of prazosin and yohimbine on peripherally administered noradrenaline- (A) and phenylephrine- (B) induced thermal hyperalgesia. Groups of mice were pretreated with prazosin (1 mg/kg IP) and yohimbine (2.5 mg/kg IP) 20 min before the injection of noradrenaline (30 µg) (A) and phenylephrine (30 µg) (B) into the tail and tested in the tail-flick assay at the indicated time at the injection site. Data expressed as mean ± sem. n = 6–8 per group.*P < 0.05 significantly different from noradrenaline (30 µg) and phenylephrine (30 µg) alone.
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DISCUSSION
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In the present study, we demonstrated that the local intradermal injection of NE and phenylephrine induces local thermal hyperalgesia that can be blocked by an -1 AR antagonist. The local injection of clonidine and agmatine produced antinociception that can be blocked by -2 AR antagonists. Thus, the results of this study suggest that peripheral -1 AR activation mediates thermal hyperalgesia. In contrast, peripheral -2 AR activation mediates thermal antinociception.
The findings of the present study demonstrate that neither systemic injection of prazosin nor yohimbine alone is able to change the heat pain threshold in skin. The lack of effect of -1 and -2 AR antagonists by themselves on the heat pain threshold is consistent with previous reports demonstrating that the sympathetic system usually does not maintain tonic control over nociception in normal skin (2,14). In support of this view, it has been reported that the release of endogenous stores of NE in normal skin by tyramine, which exclusively interferes with peripheral postganglionic sympathetic neurons, did not change the heat pain threshold (15). In our study, we observed thermal hyperalgesic action after intradermal injections of NE and phenylephrine. In rats, the level of NE in skin is approximally 85 ng/g in normal conditions (16). In our experiment, the amounts of NE injected into the tail to elicit thermal hyperalgesia was 10 µg and 30 µg. Although we were not able to measure the actual concentration of NE that reaches sensory terminals in the skin, the injected doses of NE seem well above the physiological range. However, in pathological pain states such as neuropathic pain and inflammation, most primary afferents, including nociceptors, can develop sensitivity to NE (17). Consistent with the results of our study, previous studies have shown that local administration of large doses of NE and phenylephrine increase the sensitivity of human skin to heat (7). The thermal hyperalgesic effects of NE and phenylephrine were blocked by pretreatment with prazosin, an -1 AR antagonist, whereas the -2 AR antagonist, yohimbine, was without effect in this regard. Thus, local thermal hyperalgesic effects of NE and phenylephrine are mediated by peripheral -1 AR.
We showed that the local injection of clonidine produced peripheral antinociceptive effects and that this effect was blocked by yohimbine, whereas prazosin was without effect. Thus, our results indicate that peripheral -2 AR can mediate antinociception induced by clonidine. These observations are consistent with a previous report that yohimbine at the same dose used in this study selectively reverses the topical antinociceptive effects of clonidine (8). In this study, we observed that agmatine, an identified endogenous ligand for imidazoline receptors, produced antinociceptive effects when given locally. Agmatine is an endogenous imidazoline receptor agonist, but it has been reported that it also binds -2 AR. It has been known that yohimbine is a selective -2 AR antagonist and that it is devoid of affinity for the imidazoline receptor, even at large concentrations (18). Thus, in this study, the same dose of yohimbine, which blocked the peripheral antinociceptive effects of clonidine, inhibited agmatine’s peripheral antinociception and confirmed the importance of the -2 AR in agmatine-induced peripheral antinociception. Interestingly, in a previous study, it was suggested that systemic agmatine enhanced morphine-induced antinociception via the -2 AR in mice (19).
One possible interpretation of the ability of peripherally administered drugs to produce thermal hyperalgesia or antinociception is that they are diffusing into the systemic circulation and acting at spinal and supraspinal sites (20). In all cases, thermal hyperalgesic action seen with local administration of NE and phenylephrine, which does not readily cross blood-brain barrier, was limited to the region of the tail that was drug injected and was not seen in the proximal control site, thus confirming the peripheral site of action for NE and phenylephrine. In contrast to NE and phenylephrine, both clonidine and agmatine cross the blood-brain barrier (21). Thus, it is apparent that intracutaneously administered agmatine and clonidine may act at several sites, such as peripheral, spinal, and supraspinal. In the present study, the antinociceptive action seen with local administration of agmatine (3, 30, and 50 µg) and clonidine (1 and 3 µg) was limited to the region of the tail where the drugs were injected and was not seen in the proximal areas, again confirming the peripheral sites of action for agmatine and clonidine. Nevertheless, we observed an antinociceptive effect at the noninjected proximal site after local injection of the largest dose of clonidine (10 µg), thereby suggesting the potential systemic effects of clonidine at this dose. However, we noted that the antinociceptive effects at the drug-injected site were significantly more intense than at the noninjected control site. It appears that peripheral clonidine administration can produce antinociception by an action in the periphery as well as spinally and supraspinally at larger doses. In our study, we noted that the local antinociceptive potency of agmatine was lower than that of clonidine. Moreover, we observed that there was a delay in time to peak antinociceptive action of local agmatine administration when compared with clonidine. Considerable evidence suggests that agmatine acts mainly at the imidazoline receptors and has little affinity for the -2 AR (3,22). This may explain the low potency and the delay in time to peak antinociceptive action of peripherally administered agmatine when compared with local administration of clonidine.
Differential coupling of -1 and -2 AR subtypes to second messenger systems and location on different cell types in the spinal cord or skin may also explain their differential responses to AR agonist stimulation, leading to hyperalgesia and antinociception. Alpha-1 AR are characterized by their positive coupling via Gq/11 to voltage-gated Ca2+ channels and phospholipase C activation, which mobilizes intracellular pools of calcium (3,4). However, -2 AR are distinguished by their coupling via Gi/o to inhibition of adenylyl cyclase and to enhancement of K+-currents and suppression of Ca2+ currents (3). Thus, although activation of -1 AR has a facilitatory influence on neuronal excitability, -2 AR shows inhibitory influence on neuronal excitability (3). Our study confirms a fundamental difference between -1 and -2 AR coupling: that intradermal injection of -1 agonist increases and -2 agonist decreases thermal nociceptive responses.
The data presented here provide evidence for the activation of peripheral -1 and -2 AR that produce thermal hyperalgesia and antinociception, respectively. In the present study, direct evidence is lacking that peripherally injected AR agonists directly activate peripheral AR expressed on the cutaneous nociceptor. However, -1 and -2 AR are expressed by peripheral sensory neurons (1,3,13). In addition, neurophysiological experiments are consistent with the activation of AR on the primary afferent neurons after local AR agonist administration (23). Thus, we postulated that a peripherally injected AR agonist directly activates peripheral AR expressed on the cutaneous nociceptor. However, it is conceivable that locally injected AR agonists affect nociception indirectly. They can release or inhibit a diversity of chemical mediators from skin tissues that can activate or inhibit peripheral sensory nerve endings. For example, there are some studies that AR agonists release prostaglandins (7) after their local administration into the skin.
Previous studies indicate that drug-induced alterations in tail-skin temperature may significantly affect the outcome of the tail-flick test (24). In this study, we were not able to measure local tail temperature after drug administration. Thus, it may be arguable that thermal hyperalgesia associated with NE and phenylephrine is associated with vasoconstriction and a subsequent decrease in blood flow and temperature in the vicinity of nociceptor terminals. However, some evidence has excluded the possibility of vasoconstriction as a major factor leading to thermal hyperalgesia. First, clonidine, which has been reported to induce equivalent vasoconstriction with NE and phenylephrine in healthy skin (25), produced antinociceptive effects in our study. Second, it has been shown that intradermal injection of non-adrenergic vasoconstrictors, such as angiotensin and vasopressin produced vasoconstriction in the skin without any heat hyperalgesia (8). Thus, we conclude that the vasoconstriction and decrease in blood flow in the vicinity skin of the drug-injected site was not a major factor leading to the development of local thermal hyperalgesia or antinociception.
In conclusion, pronociceptive and antinociceptive actions mediated via -1 and -2 AR, respectively, after peripheral administration of an AR and imidazoline receptor agonist may account for the bidirectional influence of the stimulation of NE receptors upon nociception in the periphery.
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ACKNOWLEDGMENTS
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We thank Mike Ossipov for his critical reading and helpful suggestions.
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Footnotes
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Accepted for publication April 10, 2006.
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Abstract
Introduction
