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Importance of histamine H2 receptors in restraint-morphine interactions
Life Sciences, Vol. 57, No. 13, pp. PL 155158, 1995 Copyright @ 1995 Elscvier Science Ltd Printed in the USA. All rights reseti 0024-3205/95 $950 t .oo
Pergamon 0024-3205(95)02078-W
PHARMACOLOGY LETTERS Accelerated Communication IME’ORTANCE OF HISTAMINE Hz RECEPTORS RESTRAINT-MORPHINE INTERACTIONS
IN
Julia W. Nalwalk and Lindsay B. Hough Department of Pharmacology and Neuroscience Albany Medical College Albany, NY 12208 (SubmittedMay 4, 1995; accepted May 15, 1995; received in fmal form June 30, 1995)
The effects of the brain-penetrating Hz antagonist zolantidine (ZOL, 3 mg/kg, s.c.) were studied on morphine (MOR, 4 mg/kg, s.c.) antinociception (tail flick test) in the presence and absence of previous restraint stress. Animals were handled for 3 days (to reduce handling stress), restrained for 1 hr or handled on day 4, and tested 24 hrs later. As found previously, restraint enhanced the intensity and duration of MOR antinociception. ZOL potentiated MOR antinociception in handled, non-restrained animals, but inhibited MOR action in restrained animals. In contrast, ZOL had no effects on nociceptive responses in either handled or stressed subjects in the absence of MOR. The data suggest that, in the absence of restraint, brain HA acts at the H2 receptor to inhibit MOR antinociception. In contrast, when an animal has been previously restrained, HA enhances MOR antinociception. Thus, brain HA appears to mediate the restraintinduced potentiation of MOR antinociception. Taken with previous results, the present findings suggest that in the presence of MOR, brain HA can provide bidirectional modulation of nociception. The direction of the modulation seems to depend upon the stress experience of the animal. Abstract.
Key Words: histamine,brain H, receptor, zolantidine,antinociception,morphine
Introduction Recent findings support the hypothesis that histamine (HA) acts as a mediator of MOR-induced antinociception in the CNS. For example, intracerebral injections of HA induce antinociceptive responses that are inhibited by HZ antagonists (l-3). In addition, HA is released from the periaqueductal grey (PAG) following systemic administration of MOR (4-6). The PAG is known to be an important site for the regulation of pain transmission (7). Furthermore, HZ antagonists given systemically (8,9), into the CNS via the lateral ventricle (10) or directly into the PAG (11) inhibit MOR antinociception. The ability of H2 antagonists to inhibit MOR antinociception may depend on the amount of stress associated with nociceptive testing (12). In addition to the analgesic properties of HA, dose-response studies with HA and HA releasers (e.g. the Hs antagonist thioperamide) have revealed that, depending on the dose, HA can also produce the opposite Corresponding author: Lindsay B. Hough, Dept. Pharmacology and Neuroscience, Albany Medical College A-136, Albany, NY 12208
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response (2,3).
HA in the CNS may also play a role as a mediator of stress-induced
antinociception. Thus, when administered systemically, HZ antagonists (13,14) and inhibitors of HA synthesis (15), attenuate several forms of stress-induced antinociception. A number of HZ antagonists with varying HZ receptor affinities, administered centrally, inhibit antinociceptive responses induced by inescapable footshock (16). It is noteworthy that zolantidine (ZOL), the first brain-penetrating Hz antagonist, attenuates both “opiate” and “non-opiate” forms of footshock-induced analgesia (813). Other studies also suggest the importance of brain HA as a mediator of stress-induced alterations in brain systems (17,18).
The intensity and duration of MOR antinociception has been shown to increase dramatically by the addition of stressful experiences such as restraint (19). This phenomenon is evident even when the stressor does not change nociceptive threshold (20). The potentiation of MOR antinociception is most pronounced with mu agonists (21) depends on the CNS (22) and not the pituitary (20) and is not mediated by alterations in opiate receptor afIinity (23) or by changes in MOR levels (20). Previous work showed that a single 1 hr restraint period can potentiate MOR antinociception up to 168 hr later (24). However, the mechanism for the restraint-induced potentiation of MOR antinociception remains unclear. Since previous studies suggested a role for HA as a mediator of stress-induced antinociception and, since other recent work suggests that the HA component of MOR analgesia may be more evident during stressful test conditions (12), we further investigated the role of HA as a mediator of stressTo test the hypothesis that HZ receptors participate in the stress-induced MOR interactions. potentiation of MOR antinociception, the effects of the brain-penetrating Hz antagonist ZOL were assessed on MOR antinociception in the presence and absence of pretreatment with a single 1 hr restraint session (24). Methods Testing: A handling/restraint/testing protocol known to potentiate MOR antinociception was used (24). Male Sprague-Dawley rats (250 - 350 g; Taconic Farms, Germantown, NY) were housed 3 per cage with food and water freely available. Animals were maintained on a normal light/dark cycle (lights on 7:00, off 19:OO). Although handling is initially stressful to laboratory rats, the animals quickly adapt to daily handling. Thus, subjects were briefly handled once a day for 3 days prior to restraint to minimize stress responses in control animals. Handling consisted of gentle restraint under a laboratory bench pad while simulating tail flick (TF) testing and S.C. injection; rats were not injected nor exposed to the test apparatus at this time. On day 4, subjects were either restrained for 1 hr at room temperature using a “Broome” restrainer (2.5 in x 8.5 in, Harvard Apparatus, South Natick, MA) or handled briefly again as a control procedure. Twenty four hr later (i.e. day 5) animals were placed under the laboratory pad and the ventral surface of the tail was exposed to a radiant heat source for TF testing (25). Three baseline measurements were made at 1 min intervals with temperature settings such that baseline latencies were approximately 2 set (24). The mean of the second and third measurements were taken as the score for each subject. Animals not responding within 6 set were removed from the heat source. Rats then received combinations of MOR (4 mg sulfate salt/kg), saline, ZOL (3 mg/kg, dimaleate salt) or vehicle (sodium maleate, 1.53 mg/kg ) and single TF tests performed 20,40 and 60 min later. Drug solutions: ZOL (SmithKline Beecham, Her&ford&ire, UK), maleic acid (disodium salt, Sigma, St. Louis, MO) and MOR sulfate (Sigma) were dissolved in saline. Doses are specified as
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the salt for all drugs. ZOL and its vehicle were injected S.C. (flank); MOR and saline were administered S.C. (neck). Data Analysis: (%MPE):
Antinociceptive %MPE
scores were calculated as percent of maximum
= [MOR latency
(set)
- baseline
latency
(set)]
[cutoff latency
(set)
- baseline
latency
(set)]
possible effect
*loo
where the cutoff latency is 6 sec.. Results are given as mean %MPE + S.E.M. Repeated measures analysis of variance (ANOVA) was used to analyze O/oMPE scores, and LSD post-hoc comparisons used were appropriate (CSS Statistica Program, Tulsa, OK). All procedures were reviewed and approved by the Institutional Animal Care and Use Committee of Albany Medical College. Results
Fig. 1 Effects of the Hz antagonist ZOL and restraint on nociceptive latencies in the presence and absence of MOR. Subjects were handled (days l-3), restrained (day 4) and tested for nociception over a 5 day period as described in the text. On the fifth day, animals were tested for baseline nociceptive responses, then received MOR (4 mgkg, s.c., A, left, n=lO) or saline (B, right, n=5), along with either ZOL (3 mgkg, s.c.) or vehicle and were retested 20, 40 and 60 mm later (abscissa). Antinociceptive scores (?&fPE, mean f S.E.M.) are shown on the ordinate. Baseline latencies were not affected by restraint (2.19 f 0.05 set, n=30 in nonrestrained animals versus 2.15 k 0.05 set, n=30 in restrained animals). Treatment groups were the following: no restraint/vehicle or no restraint/Z01 (open and cross-hatched bars, respectively), restraint/vehicle or restraint/Z01 (diagonal and solid bars, respectively). A 2-factor ANOVA (restraint/no restraint, ZOL/vehicle) with repeated measures (time) performed on data from MOR-treated subjects (left) showed a significant effect of time (P < 0.001) and a significant restraint by ZOL interaction (P < 0.03). *, + P < 0.05 compared to no restraint/vehicle and restraint/vehicle control groups within the same test period, respectively.
Subjects exposed to 1 hr of restraint 24 hr prior to MOR administration displayed an enhanced intensity and duration of MOR antinociception (Fig. 1A, 20,40 and 60 min); this restraint treatment had no effect in the absence of MOR (Fig. 1B). Treatment with the Hz antagonist ZOL
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significantly reversed the restraint-induced potentiation of MOR antinociception (Fig. lA, 20 and 60 min). In contrast, the same ZOL treatment potentiuted MOR antinociception in handled, nonrestrained subjects (Fig. 1A, 20 and 40 min). ZOL treatment did not modify nociceptive responses in any of the stress groups in the absence of MOR (Fig. 1B). Discussion The enhancement of MOR antinociception 24 hr after exposure to restraint (Fig. 1A) reproduces earlier findings by others (20-24). The present results further suggest that HZ receptors play a significant role in the mechanism of this phenomenon. The HZ antagonist ZOL did not inhibit MOR antinociception when restraint stress was absent. In these animals, ZOL significantly enhanced MOR antinociception. This finding suggests that, in the absence of restraint, HA acts at HZ receptors to inhibit MOR antinociception. Conversely, the finding that ZOL inhibited MOR antinociception when animals were restrained 24 hrs earlier suggests that in stressed subjects, HA and the HZ receptor contribute to MOR antinociception. Thus, the present findings suggest that the presence or absence of prior restraint permits endogenous HA to induce either a net analgesic or hyperalgesic effect, respectively, after administration of MOR. Previous results suggest that these effects of ZOL are not due to changes in brain MOR levels, nor to pharmacological antagonism at CNS receptor sites other than Hz receptors (8). The dose of ZOL used presently (3 mg/kg) is similar to those previously found to inhibit footshock-induced and MOR-induced analgesia (8,13). A number of previous studies have shown that HZ antagonists inhibit MOR analgesia (8-12). However, the present results indicate that Hz antagonists can both potentiate and inhibit MOR antinociception, depending upon the stress state of the animal. Recent work (12) has reproduced some of the earlier findings and also expanded upon them. Thus, systemic ZOL inhibited MOR antinociception as assessed on the hot plate test, but additional results showed that the effect of ZOL depended upon various nociceptive test parameters. Thus, when a “stressful” hot plate test paradigm was employed, ZOL inhibited MOR antinociception. In contrast, the same treatment had no effect on MOR analgesia when a “low stress” hot plate procedure was used, suggesting that some “minimal” amount of stress is necessary for Hz antagonists to inhibit MOR antinociception. The “stressful” hot plate test consisted of exposure of test subjects to the warm surface for 60 set during baseline testing independent of their response latency (discussed in (12)). It should also be noted that in the present study (unlike previous studies with Hz antagonists), the non-restrained control group was repeatedly handled for 4 days to minimize the stress of handling and testing. In previous studies in which HZ antagonists were found to inhibit MOR antinociception, subjects had not been handled prior to testing, and thus were naive to both the experimenter and to the test conditions. Once again, a “minimal” amount of stress (in this case exposure to a novel test procedure) may have been necessary. In studies where HZ antagonists were administered directly into the brain (10,l l), the stress of the surgical procedure itself may have been sufficient to alter the stress state of the animal and provide a “minimal” amount of stress. Further studies employing handling of surgical animals are needed. The results in the handled, non-restrained control group imply that HA is anti-analgesic when MOR is administered. Thus, ZOL potentiated MOR antinociception in handled animals that were not exposed to restraint. While this is contrary to a number of previous findings, it should be noted that HA injected directly into the PAG can induce either antinociceptive and pro-nociceptive effects, depending upon the dose administered (2). It can thus be hypothesized that a previous stressful experience can alter the magnitude of MOR-induced HA release, which, in turn can result in either antinociceptive or pro-nociceptive modulation. Although this hypothesis has not been directly tested, an earlier experiment showed that introduction of simultaneous tail-pinch testing in an in
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vivo microdialysis experiment significantly altered the amount of HA released in the PAG by MOR (5). The experiment suggests that the stress of the nociceptive testing can alter opiate-induced HA release. The present results also support this suggestion, and provide a paradigm for separation of the opposing nociceptive and antinociceptive effects of HA in brain. The antinociceptive and pronociceptive effects of HA may be attributable to different cell types, cell populations, brain locations or mechanisms. Further studies are needed to examine how and where these effects occur. A recent study from our laboratory with the HA-depleting agent cr-fluoromethylhistidine (FMH) yielded results very similar to the present results with the HZ antagonist ZOL (26). FMH potentiated MOR antinociception in non-restrained, handled subjects, but inhibited MOR action in animals restrained with an protocol identical to that described presently. Similar results were reported by others in more severely stressed rats chronically treated with FMH (27). As with the present ZOL data, the FMH data suggest that HA contributes to the restraint stress-induced potentiation of MOR analgesia but yet inhibits MOR analgesia in non-restrained animals. In conjunction with the data presently reported, the FMH results lend support to the hypothesis that HA can have opposing roles in the modulation of nociceptive responses. Stress-induced potentiation of MOR antinociception has remained a poorly understood phenomenon. The present results suggest that exposure to stress alters MOR analgesia and that HA can play a dual role in this process. In unstressed subjects, MOR-induced HA release may reduce the efficacy of MOR. In contrast, when a subject has been previously stressed, MORinduced HA release can potentiate MOR antinociception. The present results make it clear that the neurochemical mechanisms of MOR-induced pain relief depend on an organism’s past experience with stressful stimuli. Acknowlednments We thank Dr. Rodney Young (SmithKline Beecham, He&ford&ire, UK) for the sample of zolantidine dimaleate. This work was supported by NIDA grant DA-02816. References 1. S.D. GLICK AND L.A. CRANE, Nature 273 547-549 (1978). 2. K.K. THOBURN, L.B. HOUGH, J.W. NALWALK AND S.A. MISCHLER, Pain 58 29-37 (1994). 3. P. MALMBERG-AIELLO, C. LAMBERTI, C. GHELARDINI, A. GIOTTI AND A. BARTOLINI, Br. J. Pharmacol. 111 1269-1279 (1994). 4. K.E. BARKE AND L.B. HOUGH, Brain Res. 572 146-153 (1992). 5. K.E. BARKE AND L.B. HOUGH, J. Pharm. Exp. Ther. 266 934-942 (1993). 6. K.E. BARKE AND L.B. HOUGH, J. Neurochem. 63 238-244 (1994). 7. A.J. BEITZ, Animal Pain, C.E. Short and A.V. Poznak (eds), 31-62, Churchill Livingston, New York (1992). 8. K.R. GOGAS, L.B. HOUGH,N.B. EBERLE,R.A. LYON, S.D. GLICK, S.J. WARD, R.C. YOUNG AND M.E. PARSONS, J. Pharmacol. Exp. Ther. 250 476-484 (1989). 9. L.B. HOUGH, J.W. NALWALK AND A.M. BATTLES, BrainRes. 526 153-155 (1990). 10. L.B. HOUGH AND J.W. NALWALK, Eur. J. Pharmacol. 2 15 69-74 (1992). 11. L.B. HOUGH AND J.W. NALWALK, Brain Res. 588 58-66 (1992). 12. J.W. NALWALK, J.E. KOCH, K.E. BARKE, R.J. BODNAR AND L.B. HOUGH, Pharmacol. Biochem. Behav. 50 421-429 (1995). 13. K.R. GOGAS AND L.B. HOUGH, Neuropharmacol. 27 357-362 (1988).
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15.
16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.
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L.B. HOUGH AND R.J. BODNAR, Pharmacol. Biochem. Behav. 3 1 107112 (1988). J.W. LEWIS, G.W. TERMAN, L.R. NELSON AND J.C. LIEBESKIND, Stress-induced Analgesia, M.D. Tricklebank and G. Curzon (eds), 103-133, John Wiley & Sons, Chichester (1984). K.R. GOGAS AND L.B. HOUGH, J. Pharmacol. Exp. Ther. 248 262-267 (1989). L.B. HOUGH, Progress in Neurobiology, Vol. 30, G.A. Kerkut and J.W. Phillis (eds), 469-505, Pergamon Press, Oxford (1988). J.C. SCHWARTZ, J.M. ARRANG, M. GARBARG, H. POLLARD AND M. RUAT, Physiol. Rev. 71 1-51 (1991). C.A. PORRO AND G. CARLI, Pain 32 289-307 (1988). B.D. APPELBAUM AND S.G. HOLTZMAN, J. Pharm. Exp. Ther. 23 1 555-565 (1984). D.J. CALCAGNETTI, S.W. FLEETWOOD AND S.G. HOLTZMAN, Pharmacol. Biochem. Behav. 37 193-199 (1990). B.D. APPELBAUM AND S.G. HOLTZMAN, Brain Res. 358 303-308 (1985). B.D. APPELBAUM AND S.G. HOLTZMAN, Life Sci. 36 1069-1074 (1985). D.J. CALCAGNETTI AND S.G. HOLTZMAN, Pharmacol. Biochem. Behav. 41 449-453 (1992). F.E. D’AMOUR AND D.L. SMITH, J. Pharmacol. Exp. Ther. 72 74-79 (1941). L.B. HOUGH AND J.W. NALWALK, Inflammation Research 44 (Supplement 1) 540-541 (1995). R. ARRIGO-REINA, Agents Actions 30 210-212 (1990).
Pergamon 0024-3205(95)02078-W
PHARMACOLOGY LETTERS Accelerated Communication IME’ORTANCE OF HISTAMINE Hz RECEPTORS RESTRAINT-MORPHINE INTERACTIONS
IN
Julia W. Nalwalk and Lindsay B. Hough Department of Pharmacology and Neuroscience Albany Medical College Albany, NY 12208 (SubmittedMay 4, 1995; accepted May 15, 1995; received in fmal form June 30, 1995)
The effects of the brain-penetrating Hz antagonist zolantidine (ZOL, 3 mg/kg, s.c.) were studied on morphine (MOR, 4 mg/kg, s.c.) antinociception (tail flick test) in the presence and absence of previous restraint stress. Animals were handled for 3 days (to reduce handling stress), restrained for 1 hr or handled on day 4, and tested 24 hrs later. As found previously, restraint enhanced the intensity and duration of MOR antinociception. ZOL potentiated MOR antinociception in handled, non-restrained animals, but inhibited MOR action in restrained animals. In contrast, ZOL had no effects on nociceptive responses in either handled or stressed subjects in the absence of MOR. The data suggest that, in the absence of restraint, brain HA acts at the H2 receptor to inhibit MOR antinociception. In contrast, when an animal has been previously restrained, HA enhances MOR antinociception. Thus, brain HA appears to mediate the restraintinduced potentiation of MOR antinociception. Taken with previous results, the present findings suggest that in the presence of MOR, brain HA can provide bidirectional modulation of nociception. The direction of the modulation seems to depend upon the stress experience of the animal. Abstract.
Key Words: histamine,brain H, receptor, zolantidine,antinociception,morphine
Introduction Recent findings support the hypothesis that histamine (HA) acts as a mediator of MOR-induced antinociception in the CNS. For example, intracerebral injections of HA induce antinociceptive responses that are inhibited by HZ antagonists (l-3). In addition, HA is released from the periaqueductal grey (PAG) following systemic administration of MOR (4-6). The PAG is known to be an important site for the regulation of pain transmission (7). Furthermore, HZ antagonists given systemically (8,9), into the CNS via the lateral ventricle (10) or directly into the PAG (11) inhibit MOR antinociception. The ability of H2 antagonists to inhibit MOR antinociception may depend on the amount of stress associated with nociceptive testing (12). In addition to the analgesic properties of HA, dose-response studies with HA and HA releasers (e.g. the Hs antagonist thioperamide) have revealed that, depending on the dose, HA can also produce the opposite Corresponding author: Lindsay B. Hough, Dept. Pharmacology and Neuroscience, Albany Medical College A-136, Albany, NY 12208
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response (2,3).
HA in the CNS may also play a role as a mediator of stress-induced
antinociception. Thus, when administered systemically, HZ antagonists (13,14) and inhibitors of HA synthesis (15), attenuate several forms of stress-induced antinociception. A number of HZ antagonists with varying HZ receptor affinities, administered centrally, inhibit antinociceptive responses induced by inescapable footshock (16). It is noteworthy that zolantidine (ZOL), the first brain-penetrating Hz antagonist, attenuates both “opiate” and “non-opiate” forms of footshock-induced analgesia (813). Other studies also suggest the importance of brain HA as a mediator of stress-induced alterations in brain systems (17,18).
The intensity and duration of MOR antinociception has been shown to increase dramatically by the addition of stressful experiences such as restraint (19). This phenomenon is evident even when the stressor does not change nociceptive threshold (20). The potentiation of MOR antinociception is most pronounced with mu agonists (21) depends on the CNS (22) and not the pituitary (20) and is not mediated by alterations in opiate receptor afIinity (23) or by changes in MOR levels (20). Previous work showed that a single 1 hr restraint period can potentiate MOR antinociception up to 168 hr later (24). However, the mechanism for the restraint-induced potentiation of MOR antinociception remains unclear. Since previous studies suggested a role for HA as a mediator of stress-induced antinociception and, since other recent work suggests that the HA component of MOR analgesia may be more evident during stressful test conditions (12), we further investigated the role of HA as a mediator of stressTo test the hypothesis that HZ receptors participate in the stress-induced MOR interactions. potentiation of MOR antinociception, the effects of the brain-penetrating Hz antagonist ZOL were assessed on MOR antinociception in the presence and absence of pretreatment with a single 1 hr restraint session (24). Methods Testing: A handling/restraint/testing protocol known to potentiate MOR antinociception was used (24). Male Sprague-Dawley rats (250 - 350 g; Taconic Farms, Germantown, NY) were housed 3 per cage with food and water freely available. Animals were maintained on a normal light/dark cycle (lights on 7:00, off 19:OO). Although handling is initially stressful to laboratory rats, the animals quickly adapt to daily handling. Thus, subjects were briefly handled once a day for 3 days prior to restraint to minimize stress responses in control animals. Handling consisted of gentle restraint under a laboratory bench pad while simulating tail flick (TF) testing and S.C. injection; rats were not injected nor exposed to the test apparatus at this time. On day 4, subjects were either restrained for 1 hr at room temperature using a “Broome” restrainer (2.5 in x 8.5 in, Harvard Apparatus, South Natick, MA) or handled briefly again as a control procedure. Twenty four hr later (i.e. day 5) animals were placed under the laboratory pad and the ventral surface of the tail was exposed to a radiant heat source for TF testing (25). Three baseline measurements were made at 1 min intervals with temperature settings such that baseline latencies were approximately 2 set (24). The mean of the second and third measurements were taken as the score for each subject. Animals not responding within 6 set were removed from the heat source. Rats then received combinations of MOR (4 mg sulfate salt/kg), saline, ZOL (3 mg/kg, dimaleate salt) or vehicle (sodium maleate, 1.53 mg/kg ) and single TF tests performed 20,40 and 60 min later. Drug solutions: ZOL (SmithKline Beecham, Her&ford&ire, UK), maleic acid (disodium salt, Sigma, St. Louis, MO) and MOR sulfate (Sigma) were dissolved in saline. Doses are specified as
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the salt for all drugs. ZOL and its vehicle were injected S.C. (flank); MOR and saline were administered S.C. (neck). Data Analysis: (%MPE):
Antinociceptive %MPE
scores were calculated as percent of maximum
= [MOR latency
(set)
- baseline
latency
(set)]
[cutoff latency
(set)
- baseline
latency
(set)]
possible effect
*loo
where the cutoff latency is 6 sec.. Results are given as mean %MPE + S.E.M. Repeated measures analysis of variance (ANOVA) was used to analyze O/oMPE scores, and LSD post-hoc comparisons used were appropriate (CSS Statistica Program, Tulsa, OK). All procedures were reviewed and approved by the Institutional Animal Care and Use Committee of Albany Medical College. Results
Fig. 1 Effects of the Hz antagonist ZOL and restraint on nociceptive latencies in the presence and absence of MOR. Subjects were handled (days l-3), restrained (day 4) and tested for nociception over a 5 day period as described in the text. On the fifth day, animals were tested for baseline nociceptive responses, then received MOR (4 mgkg, s.c., A, left, n=lO) or saline (B, right, n=5), along with either ZOL (3 mgkg, s.c.) or vehicle and were retested 20, 40 and 60 mm later (abscissa). Antinociceptive scores (?&fPE, mean f S.E.M.) are shown on the ordinate. Baseline latencies were not affected by restraint (2.19 f 0.05 set, n=30 in nonrestrained animals versus 2.15 k 0.05 set, n=30 in restrained animals). Treatment groups were the following: no restraint/vehicle or no restraint/Z01 (open and cross-hatched bars, respectively), restraint/vehicle or restraint/Z01 (diagonal and solid bars, respectively). A 2-factor ANOVA (restraint/no restraint, ZOL/vehicle) with repeated measures (time) performed on data from MOR-treated subjects (left) showed a significant effect of time (P < 0.001) and a significant restraint by ZOL interaction (P < 0.03). *, + P < 0.05 compared to no restraint/vehicle and restraint/vehicle control groups within the same test period, respectively.
Subjects exposed to 1 hr of restraint 24 hr prior to MOR administration displayed an enhanced intensity and duration of MOR antinociception (Fig. 1A, 20,40 and 60 min); this restraint treatment had no effect in the absence of MOR (Fig. 1B). Treatment with the Hz antagonist ZOL
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significantly reversed the restraint-induced potentiation of MOR antinociception (Fig. lA, 20 and 60 min). In contrast, the same ZOL treatment potentiuted MOR antinociception in handled, nonrestrained subjects (Fig. 1A, 20 and 40 min). ZOL treatment did not modify nociceptive responses in any of the stress groups in the absence of MOR (Fig. 1B). Discussion The enhancement of MOR antinociception 24 hr after exposure to restraint (Fig. 1A) reproduces earlier findings by others (20-24). The present results further suggest that HZ receptors play a significant role in the mechanism of this phenomenon. The HZ antagonist ZOL did not inhibit MOR antinociception when restraint stress was absent. In these animals, ZOL significantly enhanced MOR antinociception. This finding suggests that, in the absence of restraint, HA acts at HZ receptors to inhibit MOR antinociception. Conversely, the finding that ZOL inhibited MOR antinociception when animals were restrained 24 hrs earlier suggests that in stressed subjects, HA and the HZ receptor contribute to MOR antinociception. Thus, the present findings suggest that the presence or absence of prior restraint permits endogenous HA to induce either a net analgesic or hyperalgesic effect, respectively, after administration of MOR. Previous results suggest that these effects of ZOL are not due to changes in brain MOR levels, nor to pharmacological antagonism at CNS receptor sites other than Hz receptors (8). The dose of ZOL used presently (3 mg/kg) is similar to those previously found to inhibit footshock-induced and MOR-induced analgesia (8,13). A number of previous studies have shown that HZ antagonists inhibit MOR analgesia (8-12). However, the present results indicate that Hz antagonists can both potentiate and inhibit MOR antinociception, depending upon the stress state of the animal. Recent work (12) has reproduced some of the earlier findings and also expanded upon them. Thus, systemic ZOL inhibited MOR antinociception as assessed on the hot plate test, but additional results showed that the effect of ZOL depended upon various nociceptive test parameters. Thus, when a “stressful” hot plate test paradigm was employed, ZOL inhibited MOR antinociception. In contrast, the same treatment had no effect on MOR analgesia when a “low stress” hot plate procedure was used, suggesting that some “minimal” amount of stress is necessary for Hz antagonists to inhibit MOR antinociception. The “stressful” hot plate test consisted of exposure of test subjects to the warm surface for 60 set during baseline testing independent of their response latency (discussed in (12)). It should also be noted that in the present study (unlike previous studies with Hz antagonists), the non-restrained control group was repeatedly handled for 4 days to minimize the stress of handling and testing. In previous studies in which HZ antagonists were found to inhibit MOR antinociception, subjects had not been handled prior to testing, and thus were naive to both the experimenter and to the test conditions. Once again, a “minimal” amount of stress (in this case exposure to a novel test procedure) may have been necessary. In studies where HZ antagonists were administered directly into the brain (10,l l), the stress of the surgical procedure itself may have been sufficient to alter the stress state of the animal and provide a “minimal” amount of stress. Further studies employing handling of surgical animals are needed. The results in the handled, non-restrained control group imply that HA is anti-analgesic when MOR is administered. Thus, ZOL potentiated MOR antinociception in handled animals that were not exposed to restraint. While this is contrary to a number of previous findings, it should be noted that HA injected directly into the PAG can induce either antinociceptive and pro-nociceptive effects, depending upon the dose administered (2). It can thus be hypothesized that a previous stressful experience can alter the magnitude of MOR-induced HA release, which, in turn can result in either antinociceptive or pro-nociceptive modulation. Although this hypothesis has not been directly tested, an earlier experiment showed that introduction of simultaneous tail-pinch testing in an in
Vol. 57, No. 13, 1995
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vivo microdialysis experiment significantly altered the amount of HA released in the PAG by MOR (5). The experiment suggests that the stress of the nociceptive testing can alter opiate-induced HA release. The present results also support this suggestion, and provide a paradigm for separation of the opposing nociceptive and antinociceptive effects of HA in brain. The antinociceptive and pronociceptive effects of HA may be attributable to different cell types, cell populations, brain locations or mechanisms. Further studies are needed to examine how and where these effects occur. A recent study from our laboratory with the HA-depleting agent cr-fluoromethylhistidine (FMH) yielded results very similar to the present results with the HZ antagonist ZOL (26). FMH potentiated MOR antinociception in non-restrained, handled subjects, but inhibited MOR action in animals restrained with an protocol identical to that described presently. Similar results were reported by others in more severely stressed rats chronically treated with FMH (27). As with the present ZOL data, the FMH data suggest that HA contributes to the restraint stress-induced potentiation of MOR analgesia but yet inhibits MOR analgesia in non-restrained animals. In conjunction with the data presently reported, the FMH results lend support to the hypothesis that HA can have opposing roles in the modulation of nociceptive responses. Stress-induced potentiation of MOR antinociception has remained a poorly understood phenomenon. The present results suggest that exposure to stress alters MOR analgesia and that HA can play a dual role in this process. In unstressed subjects, MOR-induced HA release may reduce the efficacy of MOR. In contrast, when a subject has been previously stressed, MORinduced HA release can potentiate MOR antinociception. The present results make it clear that the neurochemical mechanisms of MOR-induced pain relief depend on an organism’s past experience with stressful stimuli. Acknowlednments We thank Dr. Rodney Young (SmithKline Beecham, He&ford&ire, UK) for the sample of zolantidine dimaleate. This work was supported by NIDA grant DA-02816. References 1. S.D. GLICK AND L.A. CRANE, Nature 273 547-549 (1978). 2. K.K. THOBURN, L.B. HOUGH, J.W. NALWALK AND S.A. MISCHLER, Pain 58 29-37 (1994). 3. P. MALMBERG-AIELLO, C. LAMBERTI, C. GHELARDINI, A. GIOTTI AND A. BARTOLINI, Br. J. Pharmacol. 111 1269-1279 (1994). 4. K.E. BARKE AND L.B. HOUGH, Brain Res. 572 146-153 (1992). 5. K.E. BARKE AND L.B. HOUGH, J. Pharm. Exp. Ther. 266 934-942 (1993). 6. K.E. BARKE AND L.B. HOUGH, J. Neurochem. 63 238-244 (1994). 7. A.J. BEITZ, Animal Pain, C.E. Short and A.V. Poznak (eds), 31-62, Churchill Livingston, New York (1992). 8. K.R. GOGAS, L.B. HOUGH,N.B. EBERLE,R.A. LYON, S.D. GLICK, S.J. WARD, R.C. YOUNG AND M.E. PARSONS, J. Pharmacol. Exp. Ther. 250 476-484 (1989). 9. L.B. HOUGH, J.W. NALWALK AND A.M. BATTLES, BrainRes. 526 153-155 (1990). 10. L.B. HOUGH AND J.W. NALWALK, Eur. J. Pharmacol. 2 15 69-74 (1992). 11. L.B. HOUGH AND J.W. NALWALK, Brain Res. 588 58-66 (1992). 12. J.W. NALWALK, J.E. KOCH, K.E. BARKE, R.J. BODNAR AND L.B. HOUGH, Pharmacol. Biochem. Behav. 50 421-429 (1995). 13. K.R. GOGAS AND L.B. HOUGH, Neuropharmacol. 27 357-362 (1988).
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