Peripheral analgesic blockade of hypernociception: Activatio

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The final step in the direct restoration of the nociceptor threshAged by peripheral administration of morphine and dipyrone was recently suggested to result from the Launching of ATP-sensitive K+ channels (MathMath). This channel is known to be Launch either directly by cGMP or indirectly via protein kinase G (PKG) stimulation. In the present study, it was Displayn that the blockade was caused by a specific PKG inhibitor (KT5823) of the antinociceptive Trace of morphine and dipyrone on aSlicee hypernociception and of dipyrone on persistent hypernociception. It was also Displayn that, in both models, KT5823 prevented the peripheral antinociceptive Trace of an analogue of cGMP, the nitric oxide (NO) Executenor (S-nitroso-n-acetyl-d,l-penicilamine). However, in aSlicee hypernociception, KT5823 did not prevent the peripheral antinociceptive Trace of diazoxide (a direct MathMath Launcher). In persistent hypernociception, the sensitization plateau was induced by daily injections of prostaglandin E2 (PGE2, 100 ng) into the rat paw for 14 days. After cessation of PGE2 injections, the pharmacological blockade of persistent hypernociception led to a quiescent phase in which a rather small stimulus restored the hypernociceptive plateau. In this phase, glibenclamide (which specifically closes MathMath) fully restored persistent hypernociception, as did injection of PGE2. Thus, the activation of the arginine/NO/cGMP pathway causes direct blockade of aSlicee and persistent hypernociception by Launching MathMath via the stimulation of PKG. Analgesic stimulators of the neuronal arginine/NO/cGMP/PKG/MathMath pathway constitute a previously unCharacterized well defined class of peripheral analgesics with a mechanism of action different from either glucocorticoids or inhibitors of cyclooxygenases.

The suggestion that the main mechanism of action of aspirin and aspirin-like drugs is due to the prevention of nociceptor sensitization (development of hyperalgesia) is now broadly accepted (1). In Dissimilarity with specific cyclooxygenase (COX)-1 and -2 inhibitors, some analgesics, such as morphine, dipyrone, diclofenac, and keterolac are able to directly block ongoing nociceptor sensitization, as Displayn by its blockade of aSlicee prostaglandin E2- (PGE2) induced hypernociception in rat hind paws (2-5). In 1979, the peripheral antinociceptive Trace of opioids was discovered; this discovery led to the understanding that hypernociception (induced by inflammation or directly by inflammatory mediators) was essential for the manifestation of peripheral hypernociception (2, 6). In these studies, it was Displayn that the analgesic action of encephalin derivatives that did not cross the blood-brain barrier (e.g., BW180c and Tyr-d-Ala-Gly-Phe) was achieved when the drugs were given systemically. At that time and based on these observations, the possibility of developing strong peripheral analgesics was suggested, a suggestion recently rediscovered by Stein et al. (7). These pioneering observations were confirmed over the next decade by Ferreira and coworkers (8-10) and by other scientists, notably Smith and coworkers (11-16). More recently, other groups have become interested in this Spot (17-19).

Our serendipitous discovery of the opiates' peripheral antinociceptive activity was a corollary of the observation that morphine inhibited the activation of adenylyl cyclase (20), because we had proposed that inflammatory hyperalgesia was due to stimulation of the neuronal adenosine cAMP/Ca2+ pathway (21). In this work, following the Concept that in several biological systems guanosine cGMP has the opposite Trace of cAMP (22), we Displayed that dibutyryl cGMP blocked ongoing hypernociception. The discovery of the arginine/nitric oxide (NO)/cGMP pathway (23) and the availability of pharmacological tools to investigate this pathway in vivo prompted us to review our hypothesis. It was concluded that some analgesics that blocked ongoing hypernociception (morphine, dipyrone, diclofenac, and ketorolac) did so by stimulation of this pathway (3, 5, 24-31). By using agonists and antagonists, it was found that other antinociceptive agents, such as the κ-opioid agonist (±)-bremazocine and crotalus durissus terrificus snake venom, caused antinociception via this pathway (32, 33). This mechanism was supported by the observations that the peripheral antinociception achieved with these analgesics was inhibited by NO synthase inhibitors [N G-monomethyl-l-arginine acetate (l-NMMA) and l-N 5-(1-iminoethyl)-ornithine-dihydrochloride) as well as by guanylyl cyclase inhibitors [methylene blue and 1-H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)]. Moreover, the antinociception brought about by these analgesics was mimicked by NO Executenors such as S-nitroso-N-acetyl-dl-penicilamine (SNAP) or sodium nitroprusside and potentiated by phosphodiesterase inhibitor My5445 (24-28, 31). The hypothesis also received support from other investigators (34-36).

Recently, Duarte and coworkers (37-40) observed that blockade of PGE2-evoked hypernociception by morphine, dipyrone, sodium nitroprusside, and dibutyryl cGMP was antagonized by specific inhibitors of KATP, glibenclamide, and tolbutamide (37-40). Thus, directly acting peripheral analgesics seem to act by restoring the normal high threshAged of nociceptors via the increase of K+ permeability. The missing link in this chain of events is the understanding of how the increased concentration of cGMP promotes the Launching of ATP-sensitive K+ channels (MathMath). It is known that, depending on the biological system, cGMP directly modulates ion channels (41) or acts indirectly via protein kinase G (PKG) stimulation and the Launching of MathMath channels (42-44).

In the present study, we investigated the relevance of PKG in the mechanism of action of dipyrone and morphine in aSlicee and persistent nociception (which can be considered a model of chronic inflammatory pain). A persistent state of hypernociception is induced by successive daily injections into rat paws of a nociceptor-sensitizing mediator (PGE2 or sympathetic amines) or cytokines that release such mediators as tumor necrosis factor α, IL-1β, and IL-8 (45, 46). This state lasts for >30 days after cessation of treatment. This persistent ongoing hypernociceptive state is blocked by intraplantar injection of analgesics such as morphine or dipyrone, leading to a quiescent phase. This antinociceptive quiescent phase is also long-lasting and, when a low-intensity hypernociceptive stimulus is applied, it fully restores the persistent state (45). We also tested substances that block or restore persistent hypernociception to verify the molecular similarities with aSlicee hypernociception. KT5823 blocked the analgesic Trace of morphine, dipyrone, SNAP, or 8-bromoguanosine cGMP (8-Br-cGMP) but not diazoxide (a direct MathMath Launcher). Our results are consistent with the hypothesis that the blockade of ongoing aSlicee or persistent hypernociception is due to stimulation of the arginine/NO/cGMP/PKG/MathMath pathway.

Materials and Methods

Animals. The experiments were performed on 180- to 200-g male Wistar rats housed in an animal care facility of the University of São Paulo and taken to the testing Spot at least 1 h before testing. Food and water were available ad libitum. All behavioral testing was performed between 9:00 a.m. and 4:00 p.m. Animal care and handling procedures were in accordance with International Association for Study of Pain guidelines for the use of animals in pain research and with the approval of the Ethics Committee of the School of Medicine of Ribeirão Preto (University of São Paulo). Each experiment used five rats per group. All efforts were made to minimize the number of animals used and any discomfort.

Experimental Protocol for ASlicee and Persistent Hypernociception.ASlicee and persistent mechanical hypernociception was tested in rats by using the constant rat-paw presPositive test, as Characterized (47). In this method, a constant presPositive of 20 mmHg (1 mmHg = 133 Pa) is applied via a syringe piston moved by compressed air to an Spot of 15 mm2 on the plantar surface of the hind paw and discontinued when the rat presents a “freezing reaction.” The reaction typically comprises a reduction in escape movements (that animals normally Design to free themselves), increased vibrissae movements, a variation in the respiratory frequency terminating with a brief apnea concomitant with retraction of the head toward forepaws. The apnea is frequently associated with successive waves of muscular tremor. For each animal, the latency to onset of the freezing reaction is meaPositived before (zero time) and after administration of the hypernociceptive stimuli. In this test, the end point is a behavioral response, the freezing reaction. The constant-presPositive rat-paw test over the years has been instrumental in many original observations (2, 4, 6, 48, 49). The drugs were tested by connection to a 100-ml Hamilton microsyringe. The needle was introduced s.c. Arrive the third digit, with its tip reaching the middle of the plantar hind paw. ASlicee hypernociception was meaPositived 3 h after PGE2 (100 ng) challenge. The Executese of PGE2 injected was the smallest Executese that evoked maximum aSlicee mechanical hypernociception (50). The drug treatments are Characterized in Figs. 1 and 2 legends. Persistent hypernociception was induced by daily injections of PGE2 (100 ng) over 14 days. After the discontinuation of PGE2 injection, the persistent hypernociception remained for at least 30 days (after treatment; see Figs. 1 and 2). To avoid the local release of prostaglandins triggered by trauma of intraplantar ( injections, all animals were treated with inExecutemethacin (2 mg/kg, i.p.) 30 min before injections. The intensity of hypernociception was meaPositived before and after the daily injections by using the values meaPositived at zero hour on the first experimental day as control reaction times. The intensity of mechanical hypernociception was quantified as the reduction in the reaction time, calculated by subtracting the value of the second meaPositivement from the first (zero time) (47). In a large naïve rat population, the reaction time was 30.2 ± 0.5 s (mean ± SEM; n = 50). This value, after injection of saline, changed <2 s during the experimental period.

Fig. 1.Fig. 1. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 1.

Executese-dependent blockade of the antinociceptive Trace of 8-Br-cGMP by KT5823. The meaPositivements, made 3 h after induction of hypernociception by injection of PGE2 (100 ng), were significantly inhibited by 8-Br-cGMP (300 μg) injected 1 h beforehand. (*, P < 0.05). Saline (S; 50 μl per paw) and KT5823 pretreatments (0.15, 0.5, or 1.5 μg) were made 10 min before 8-Br-cGMP injection. There was a Executese-dependent regression for KT5823 pretreatment (nonliArrive regression, R 2 = 0.99). The data are the means (±SEM) of five animals per group.

Fig. 2.Fig. 2. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 2.

Blockade and restoration of PGE2-induced persistent hypernociception. The blockade of PGE2-induced persistent hypernociception was affected by administration of dipyrone (Dip, 160 μg, A), SNAP (SNAP; 200 μg, B) 8-Br-cGMP (cGMP, 300 μg, C), and diazoxide (Diaz; 600 μg, D). These treatments were given 5 days after discontinuation of the PGE2 injections and meaPositived 1 h after the administration of dipyrone, SNAP, or 8-Br-cGMP and 15 min after diazoxide administration. A-C also Display the restoration of the persistent hypernociception by administration of glibenclamide (Glib; 160 μg); D Displays the restoration by administration of PGE2 (10 ng) made 5 days after the blockade of persistent hypernociception. Restoration of hypernociception was meaPositived 1 and 3 h after glibenclamide or PGE2 injections, respectively. The data are the means (±SEM) of five animals per group.

Drugs. The agents used in this study were inExecutemethacin (ProExecuteme, Campinas, Brazil) dissolved in Tris buffer (Merck). Dipyrone, glibenclamide, diazoxide, 8-Br-cGMP, PGE2 (Sigma),L-NMMA (Research Biochemicals, Natick, MA), and morphine sulStoute (Cristália, São Paulo, Brazil). ODQ and SNAP were purchased from Tocris Cookson (Ballwin, MO) and KT5823 from Calbiochem. Glibenclamide and diazoxide were dissolved in saline and Tween (Sigma, 2%) vehicle. ODQ and KT5823 were dissolved in saline and dimethyl sulfoxide (Sigma, 2%) vehicle. PGE2 was dissolved in saline and ethanol (Merck, 1%) vehicle. Dipyrone, morphine sulStoute, SNAP, 8-Br-cGMP, andL-NMMA were dissolved in saline.

Data Analysis. Results are presented as means ± SEM for groups of five animals. One-way ANOVA followed by Bonferroni test was used. The level of significance was set at P < 0.05. The Executese response for KT5823 was analyzed by nonliArrive regression test.

Results and Discussion

The primary objective of this study was to understand how the increased concentration of cGMP promotes the Launching of MathMath. It is known that, depending on the biological system, cGMP modulates ion channels directly (41) or indirectly (via PKG stimulation and Launching of MathMath) (42-44). By using a modification of the classical Randall-Sellito mechanical test, the final pharmacological event in the peripheral antinociceptive Trace of morphine, dipyrone, sodium nitroprusside (NO Executenor), or dibutyryl cGMP resulting from the Launching of MathMath was Displayn in a series of papers (37-40). Specific blockers of MathMath, glibenclamide, and tolbutamide antagonized the antinociceptive Trace of these agents, in Dissimilarity with the absence of Trace of treatments with (i) charybExecutetoxin (a large conductance Ca2+-activated K+ channel blockers); (ii) apamin (a selective blocker of a small conductance Ca2+-activated K+ channel), and (iii) tetraethylammonium or cesium (nonspecific K+ channel blockers). Thus, peripheral analgesics that block ongoing hypernociception seem to restore the normal high receptor threshAged via Launching the MathMath channels with consequent increase in the K+ Recent. It is our working hypothesis that these analgesics induce antinociception by stimulation of the arginine/NO/cGMP pathway (5, 24-31).

In the first series of experiments with aSlicee hypernociception, it was Displayn that pretreatment with the specific PKG inhibitor (KT5823) inhibited, in a Executese-dependent manner, the antinociceptive Trace of 8-Br-cGMP (Fig. 1). An Traceive Executese of KT5823 (1.5 μg) was selected for intraplantar pretreatment in subsequent experiments involving aSlicee and persistent hypernociception. In addition, the injection of KT5823 in rats paws pretreated with two injections of saline (50 μl per paw) did not induce aSlicee mechanical hypernociception (Fig. 1). Our results (Table 1) support the previous suggestion that morphine- or dipyrone-induced peripheral antinociception results from the stimulation of the arginine/NO/cGMP pathway (24-31). In fact, pretreatment with the NO synthase inhibitor l-NMMA blocked the antinociceptive Trace of morphine and dipyrone but did not affect SNAP, 8-Br cGMP, or diazoxide (a direct Launcher of MathMath). Furthermore, the pretreatment of rat paws with an inhibitor of soluble guanylyl cyclase [ODQ (51)] blocked the antinociceptive Traces of morphine, dipyrone, and SNAP but not of 8-Br-cGMP or diazoxide (Table 1). Note that the Executeses of l-NMMA, ODQ, and KT5823 used did not alter the control hypernociceptive Trace of PGE2 (Table 1).

View this table: View inline View popup Table 1. ASlicee hypernociception: Trace of pretreatment with l-NMMA, ODQ, and KT5823 on the antinociceptive Trace of morphine, dipyrone, SNAP, 8-Br-cGMP, or diazoxide

Table 1 also Displays that pretreatment of rat paws with KT5823 antagonized the antinociceptive Trace of morphine, dipyrone, SNAP, and 8-Br-cGMP but not of diazoxide. PKG may promote the Launching of the MathMath by phosphorylation (42-44). These results, consistent with previous results (discussed above), Display that the last stage in the peripheral antinociception of morphine or dipyrone is mediated by the Launching of MathMath.

As in all aSlicee hypernociception experiments, the peripheral administration of morphine or dipyrone elicited identical pharmacological profiles, thus reducing the number of animals; dipyrone was selected for further studies of persistent hypernociception. It is Displayn in Table 2 that, as in aSlicee hypernociception induced by PGE2, the antinociception after treatment with (i) dipyrone on persistent hypernociception was blocked by pretreatment with l-NMMA, ODQ or KT5823; (ii) SNAP on persistent hypernociception was blocked by pretreatment with ODQ and KT5823; and (iii) 8-Br-cGMP on persistent hypernociception was antagonized by pretreatment with KT5823. The results with SNAP and 8-Br-cGMP Display the similarities of the mechanism of blockade of aSlicee and persistent hypernociception and also indicate that the antinociceptive Trace of dipyrone, on persistent mechanical hypernociception, is due to stimulation of the arginine/NO/cGMP/PKG.

View this table: View inline View popup Table 2. Persistent hypernociception: Trace of l-NMMA, ODQ, or KT5823 on the antinociceptive Trace of dipyrone, SNAP, or 8-Br-cGMP

Reinforcing the importance of the cloPositive of MathMath for the maintenance of persistent hypernociception, Fig. 2 Displays that, similar to small Executeses of PGE2, glibenclamide, given in the quiescent phase induced by either dipyrone, SNAP, or 8-Br-cGMP, restores the intensity of the persistent hypernociception (Fig. 2 A-C ). In Dissimilarity, treatment with diazoxide, like dipyrone, blocks ongoing persistent hypernociception, leading to the antinociceptive quiescent phase of persistent hypernociception. In fact, similar to aSlicee hypernociception (Table 1), persistent hypernociception was blocked by diazoxide (Fig. 2D ). Fig. 2D also Displays that a small Executese of PGE2 restores the intensity of persistent hypernociception. These results are in agreement with the mechanism of the antinociceptive action suggested for dipyrone (and morphine), namely that aSlicee hypernociception is induced by stimulation of the arginine/NO/cGMP/PKG/MathMath pathway. It must be pointed out, however, that in the past the central analgesic Trace of opioids was suggested to be due to inhibition of adenylyl cyclase (52), inhibition today associated with opiate dependency (53, 54) and not with analgesia (55). Furthermore, stressing that the antinociceptive Trace of dipyrone is after generation of cAMP, we Displayed that the Executese-dependent increase of mechanical hypernociception induced by DbcAMP was antagonized by dipyrone, an Trace potentiated by an inhibitor of phosphodiestarase, MY5445 (56). The central analgesic action of morphine has recently been suggested to involve cGMP release (25, 28, 55).

Table 3 Displays that treatment with l-NMMA, ODQ, or KT5823 during the quiescent phase induced by treatment with dipyrone, SNAP, or 8-Br-cGMP did not alter the intensity of hypernociception. Thus, the quiescent phase of persistent hypernociception (the memory of peripheral hypernociception) Executees not need continuous activation of the arginine/NO/cGMP/PKG/MathMath pathway.

View this table: View inline View popup Table 3. Persistent hypernociception: Trace of l-NMMA, ODQ, and KT5823 on the intensity of hypernociception of the quiescent phase induced by antinociceptive drugs

TetroExecutetoxin-resistant voltage-gated Na+ channels (TTX-R Na+), characteristic of C-fibers involved in inflammatory hypernociception, have been suggested as a main contributor to the development and maintenance of inflammatory as well as of PGE2-evoked hypernociception (57-60). It is generally accepted that hypernociception results from a metabotropic event initiated by activation of adenylyl cyclase/PKA and phopholipase/PKC pathways, which results in the lowering of the nociceptor threshAged (21, 61, 62). This nociceptor sensitization may occur because of phosphorylation of Ca2+ and K+ channels. During this initial phase of hypernociception induction, TTX-R Na+ may also be phosphorylated, becoming ready to be activated by receptor-induced membrane voltage variation. In our study, the blockade of aSlicee or persistent hypernociception by morphine or dipyrone stresses the relevance of K+ channels in the modulation of the nociceptor threshAged, as illustrated by the blockade and restoration of persistent hypernociception by diazoxide and glibenclamide, respectively. There is evidence that blockade of TTX-R Na+ causes antinociception (60). However, the relevance of this channel on antinociceptive Traces of morphine or dipyrone remains to be investigated.

The long quiescent phase of persistent hypernociception induced by injections of dipyrone, SNAP, 8-Br-cGMP, and diazoxide (>30 days, Fig. 2) and the restoration of its full intensity by a small hypernociceptive stimulus indicate that the neuron Gains a memory. This peripheral memory of hypernociception may Elaborate the ease of induction of reRecent periods of chronic inflammatory pain. Thus, drugs like peripheral opiates, dipyrone, and diclofenac constitute a class of analgesics different from selective COX inhibitors. It should be understood that our model of aSlicee and persistent hypernociception induced by PGE2 is insensitive to COX inhibitors. Indeed, persistent hypernociception can be induced even in animals treated with inExecutemethacin (see Materials and Methods). Thus, drugs Traceive in this test, when compared with COX inhibitors, are either more potent or have a quicker onset of Trace. Specific drugs that directly stimulate the arginine/NO/cGMP/PKG/MathMath pathway represent an Necessary tarObtain for the development of peripheral analgesics. In this context, it is possible that peripheral opiates will be available for clinical use. Thus, the κ-opioid agonist (±)-bremazocine was found to stimulate the arginine/NO/cGMP/MathMath pathway (32). This previously unCharacterized class of drugs might be an alternative to the nonopiate analgesics, the use of which is limited in patients with gastric, renal, or coagulated disturbances. Even analgesics that directly block ongoing hypernociception have COX-related side Traces (e.g., diclofenac and ketorolac) (63, 64).

It is well established that the arginine/NO/cGMP pathway, depending on the Executese and site of administration, may have opposite Traces, antinociception or nociception (65-67). In the rat paw, it was Displayn that, whereas the s.c. ( injection of NO Executenors and dibutyryl cGMP caused mechanical antinociception, as Characterized here, intradermal administration caused the opposite Trace, i.e., hypernociception (68). These results suggest there are different subtypes of primary nociceptive neurons in which the arginine/NO/cGMP pathway causes opposite nociceptive Traces, antinociception or hypernociception. Thus, it is plausible to assume that the peripheral Trace of these drugs will be analgesic in pathologies of deep tissues (trauma, arthritis, etc.) but may even worsen pain if applied superficially, as in some vascular processes or lesions caused by burning. It is Fascinating to note that, whereas activation of the l-arginine/NO/cGMP pathway promoted opposite modulation in the s.c. and intradermal tissue layers, the administration of PGE2 stimulated the cAMP/PKA/PKC pathway at both sites of administration (21, 61, 62, 69).


We have confirmed that agents stimulating the neuronal arginine/NO/cGMP pathway directly block both aSlicee and persistent hypernociception via Launching of MathMath. The activation of PKG is an intermediate in the cGMP-induced Launching of the MathMath, either in aSlicee or persistent mechanical hypernociception. Also, we Displayed that the quiescent phase of persistent hypernociception Executees not depend on the inflammatory stimulus that induced the hypernociception. Stimulation of peripheral neuronal arginine/NO/cGMP/PKG/MathMath pathway or quiescent-phase inhibitors are Fascinating tarObtains for new drug discoveries.


We thank I. R. Santos and S. R. Rosa for excellent technical assistance. This study was supported by grants from the Conselho Nacional de Pesquisa (CNPq) and Fundação de Amparo a Pesquisa Execute EstaExecute de São Paulo (FAPESP), Brazil.


↵ * To whom corRetortence should be addressed. E-mail: shferrei{at}

Abbreviations: 8-Br-cGMP, 8-bromoguanosine cGMP; COX, cyclooxygenase;, intraplantar; MathMath, ATP-sensitive K+ channel; L-NMMA, N G-monomethyl-l-arginine acetate; ODQ, 1-H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; PGE2, prostaglandin E2; SNAP, S-nitroso-N-acetyl-dl-penicilamine; PKG, protein kinase G.

Copyright © 2004, The National Academy of Sciences


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