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Effect of H1 blockers alone and in combination with morphine to produce antinociception in mice
NeuropharmacologyVol. 24, No. 1, pp. 14, Printed
1985
0028-3908/85 $3.00 + 0.00 Pergamon Press Ltd
in Great Britain
EFFECT OF H, BLOCKERS ALONE AND IN COMBINATION WITH MORPHINE TO PRODUCE ANTINOCICEPTION IN MICE C.-L. J. SUN, F. W. HUI* and J. P. HANI@ Division of Drug Biology, Food and Drug Administration, Washington, DC 20204, U.S.A. (Accepted 17 May 1984)
Smnmary-Antinociception was assessed in male CD-l mice by a modification of Haffner’s tail-clamp procedure. The H, blockers, including an ethylenediamine (pyrilamine), an ethanolamine (diphenhydramine), a phenothiazine (methdilazine), a piperazine (cyclizine) and an alkylamine (chlorpheniramine), all produced antinociception when given alone to mice and also caused potentiation when combined with morphine. Key words: antinociception, cyclizine, chlorpheniramine.
The combination for the purposes
morphine,
H, blocker, pyrilamine, diphenhydramine,
of tripelennarnine with paregoric of drug abuse has previously been
reported (Showalter and Moore, 1978), and unpublished narrative (case reports) and testimonial evidence indicates the current use or abuse of other combinations of tripelennamine with “street narcotics” by addicts. A number of investigators (Havdala, Bluhm, Blumenfeld, Malmed, Borison and Diamond, 1981; Hui, Sun, Tocus and Hanig, 1980,1983; Tagashira, Kachur and Dewey, 1982; Westrick and Spratto, 1981) have confirmed the potentiation of the effects of tripelennamine by morphine in the laboratory. Mixtures of tripelennamine and pentazocine were also reported to be misused as a combination known in the “street” as “Ts and Bs” (Showalter and Moore, 1978). Laboratory studies (Hui, Sun and Hanig, 1981) have confirmed a synergism between these two drugs and have demonstrated a synergism between morphine and pentazocine as well as between other mixed agonist-antagonists. The present study sought to confirm the initial finding of antinociception with tripelennamine alone and the potentiation of its effects by morphine and to extend investigations of the phenomenon to representative compounds of the structural classes of histamine H, blockers. This report describes results obtained with combinations of morphine with an ethylenediamine (‘pyrilamine), an ethanolamine (diphenhydramine), a phenothiazine (methdilazine), a piperazine (cyclizine) and an alkylamine (chlorpheniramine).
*Visiting Scientist, Fogarty International Center, National Institutes of Health, Bethesda, MD 20205, U.S.A. tTo whom requests for reprints should be sent.
methdilazine,
METHODS
Male mice of the CD-l strain (Charles River), weighing approx. 20 g and having free access to food and water, were used in all experiments. Each treatment group consisted of 9-14 mice. The drugs were dissolved in saline and injected subcutaneously in the medio-dorsal lumbar region of the back, with control animals receiving saline. Solutions of drug or saline were injected in a volume of 0.1 ml/10 g of body weight. Antinociception was determined by a modification of the tail-clamp method of Haffner (1929), which was validated (Bianchi and Chini, 1954) following a prescreening procedure for the threshold of pain of each animal. All screened mice were grouped according to their tail-clamp reaction times (fierce biting or striking at the noxious stimulus), which ranged from 1 to 8 sec. The screened mice were then redistributed evenly (the same number of mice at each reaction time) to each treatment group, thereby reducing the effect of the observed variation in reaction time; statistical analysis has demonstrated that this redistribution reduces the background scatter with a tighter fit of the data (small differences can be shown to be significant). The reaction time after placement of the tail-clamp at the mid-tail position was determined as the time which elapsed before the test animal successfully struck or bit the clamp. All testing for antinociception was performed 30min after administration of drug. Most control mice responded within l-5 set, whereas mice which were treated that showed analgesia responded in the 8-30-set range. If a mouse took longer than 60 set to respond, that reaction time was recorded as 60 sec.
C.-L. J. Table
I. Effect of pyrilamine
Treatment None Morphine Pyrilamine Pyrilamine Morphine + pyrilamine Morphine + pyrilamine
SUNe/ al.
on antinociception
Induced
DOS? (mg:kg) .~
Reaction time (see)
II
3.0 5.8 3.9 8.3 9.6 22.3
II 12 II I? II 12
3.0 5.0 15.0 3.0 + 5.0 3.0 + IS.0
by morphine
f 0.5 + 0.4* * 0.3 i o.s* i 0.9*,t.: +2X*,1,:
*Significantly different from value for untreated controls (P i 0.05). tSignificantly different from value for morphine alone (P ~0.05). fSignilicantly different from value for pyrilamine alone at the same dose (P < 0.05).
Morphine was obtained from Dr Arthur Jacobson of the National Institutes of Health. Pyrilamine maleate was supplied by Merck Sharp & Dohme, diphenhydramine by Parke-Davis, methdilazine HCl by Mead Johnson & Co., chlorpheniramine maleate by K & K Laboratories, Inc. and cyclizine HCI by Burroughs Wellcome Co. All values are presented as means +SEM. The differences between treatments and control were analyzed by the unpaired Student’s t-test. Any differences in P value less than 0.05 were considered statistically significant. RESULTS
Pyrilamine, given alone at a dose of 15.0 mg/kg, induced a significant increase in antinociception over the response in untreated controls, whereas the smaller dose of 5.0mg/kg did not (Table 1). When pyrilamine, at the lower dose level, was combined with morphine (3.0mg/kg), the increase in antinociception was approximately the calculated arithmetic sum of the individual effects. In contrast, the combination of morphine with the larger dose of pyrilamine was synergistic.
Table 2. Effect of diohenhvdramine Treatment
~~~~
None Morphine Diphenhydramine Diphenhydramine Morphine + diphenhydramme Morphine + diphenhydramine
As shown in Table 2, antinociception was significantly increased over the value for untreated controls when diphenhydramine was given alone at 15.0 mg/kg but not at 5.0 mg/kg. The combination of either dose with morphine caused a significant increase over values for the groups treated with a single drug, and values for the combined treatment were somewhat greater than the arithmetic sum of the individual values. Methdilazine, given alone at doses of either 2.5 or 5.0mg/kg, caused a significant increase in antinociception over the value for untreated controls (Table 3). When methidilazine, at either of these dose levels, was combined with morphine, antinociception was significantly increased over that obtained with morphine or methdilazine alone. As shown in Table 4, cyclizine given alone at 2.5, 5.0 and 15.0 mg/kg produced antinociception that was significantly greater than the value obtained for untreated controls; however, the dose-response curve appeared to be rather flat, in contrast to that for methdilazine alone (Table 3). The combination of morphine with the two smaller doses of cyclizine produced antinociception that was significantly greater than values for untreated controls or the
on antinociceotion Dose (mg/kg)
3.0 5.0 15.0 3.0 + 5.0 3.0+ 15.0
induced
bv morohine
Reaction time (set)
n
3.3 8.0 4.6 8.9 14.1 21.3
I2 I3 I3 I4 13 13
f 0.4 f 1.5: _+0.7 i 1.2* k 1.8*,t,: + 3.6*,7,x
*Significantly different from value for untreated controls (P ~0.05). different from value for morphine alone (P < 0.05). SSignificantly value for diphenhydramine alone at the same dose (P < 0.05). Table 3. Effect of methdilazine Treatment None Morphine Methdilazine Methdilazine Morphine + methdilazine Morphine + methdilazine
on antinociception Dose !mg/kg) 3.0 2.5 5.0 3.0 + 2.5 3.0 + 5.0
tsignificantly different from
induced by morphine Reaction time (see) 4.9 13.3 9.9 18.7 26.6 32.1
f f * * k i
0.7 2.7* 1.5* I .5* 5.6*,t.f: 3.4*,t,f
n II II II II I1 11
‘Significantly different from value for untreated controls (P < 0.05). tsignificantly different from value for morphine alone (P ~0.05). fSignificantly different from value for methdilazine alone at the same dose (P < 0.05).
3
H, blockers and morphine antinociception Table 4. Effect of cyclizine on antinociception Treatment ~.ll--..~. None Morphine Cyclizine Cyclidne Cyclizine Morphine + cyclizine Morphine + cyclizine Morphine + cyclizine
Dose (mgk)
induced by morphine Reaction time (se@ 3.3 f 0.4 12.4 & 2.9* 7.5 i. I .o* 8.4 2 1.4* 10.3 * 1.7* 17.9 * 1.s*,t 15.4 * 1.7*,t 33.5 + 5.7*,$,$
3.0 2.5 5.0 15.0 3.0 + 2.5 3.0 + 5.0 3.0 + 15.0
n ^~ Ii 10 10 10 10 t: 10
*Significantly different from value from untreated controls (P < 0.05). Wignificantly different from value for cyctizine alone at the same dose (P c 0.05). $Significantly different from value for morphine alone (P < 0.05).
groups given cyclizine alone, but was not significantly different from the value for the group given morphine alone, The combination of morphine with the large dose of cyclizine, however, produced a significant potentiation of antinociception. Chlo~heniramine, given alone at 15.0 mg/kg, caused a significant increase in antinoci~ption (Table 5); at the smaller dose of 5.0 mgjkg, antinociception was slightly greater than that in untreated controls but the increase was not statistically significant. The combination of morphine with the smaller dose of chlo~heniramine produced an additive effect that almost equalled the arithmetic sum of the component responses; however, the combination of morphine with the large dose of chlorpheniramine produced potentiation.
It has been demonstrated previously that tripelennamine alone, at a dose as small as 1.5 mg/kg, caused antinociception in mice (Hui et cd., 1980), and that non-effective doses of nalbuphene (2.0 mg/kg) administered together with noneffective doses of tripelennamine (OS mg/kg) produced significant analgesia in the test system. This finding was in contrast to an earlier published report (Mattila and Saarnivaara, 1968) indicating that cinnarizine, another H, blocker, reduced antinociception induced by morphine in the rabbit. The present authors also found that administration of t~~lennamine (15 mgjkg) together with morphine (2.0 mg/kg) produced an analgesic effect equal to that obtained with 8.0mg of mo~hine~kg alone (Hui et al., 1983). The present study with pyrilamine, di~henhydramine~ meth-
Table 5. Effect of chiorpheniramine Treatment _“.~_~“~_--~~~~~~ None Morphine Chlorphe~~~e Chlorpheniramine Morphine f chlo~heniramine Morphine f chlo~henir~ine
dilazine, cyclizine and chlopheniramine extends the earlier finding to include all of the representative structural classes of histamine H, blockers; e.g. antinociception was obtained when these compounds were administered alone and was potentiated when they were given in combination with morphine. These results lend credence to the extensive anecdotal reports of abuse of a variety of antihista~nes, both alone and in combination with opiates. Although a pha~acolo~cal basis has been established in animals for opiate-like activity, with respect to antinociception, for I-I, antagonists as a class, the mechanism for this action is not resolved. tee and Fennessy (1976) and Mazarkiewicz-Kwilecki and Henwood (1976) studied the relationship between narcotic addiction and histamine and showed that rats, given morphine chronically, had a significant decrease of this amine in the CNS. This depletion could be normalized by daily administration of L-histidine to the animals treated with morphine (Henwood and Mazarkiewicz-Kwil~ki, 1977). In other studies (Wong and Roberts, 1975, 1977), CNS receptors for histamine in the mouse were shown to be involved in the development of tolerance to and physical dependence on morphine. It could be speculated, at this point, that blocking the H, receptor in the CNS to produce or potentiate antinociception may be somewhat equivalent to the normal depletion of the endogenous histamine that appears to occur with the administration of morphine. Augmented antinociception induced by opiates via the histaminergic system may also be related to effects upon cyclic nucleotides and the Cazc uptake system. Foreman, Mongar, Gomperts and Garland (1974) proposed that intra~ilular cyclic AMP regulates the
on antinociception
Dose imgik) 3.0 5.0 15.0 3.0 + 5.0 3.0 + 15.0
_.
induced by morphine
Reaction time W) 5.5 f 0.6 9.5 * 1.2* 7.8 + 1.5 11.5+ 1.7” 16.3 + 3.4*,t 23.4 f 2.8*,t,f
n 11 10 11 IO 9 9
*Significantly different from value for untreated controls (P < 0.05). ~Significantly different from value for chlorpheniramine alone at the same dose (P ~0.05). fdigniticantly different from value for morphine alone (P -=z 0.05).
4
C-L. J. SUN et al. REFERENCES
Ca*+ gating mechanism
which is presumed to control of histamine. Dibutyryl guanosine secretion 3’,5’-cyclic monophosphate, when administered cen-
trally to rats, totally abolishes the responses to noxious stimuli (Cohn, Cohn and Taylor, 1978). Aufrere and Anderson (1980) noted that chronic intracerebral perfusion with the naturally-occurring nucleotide cyclic GMP produced analgesia without depression of the CNS or physical dependence. Tripelennamine has been shown to augment the release of cyclic GMP, whereas cyclic AMP was reported to antagonize analgesia induced by morphine in both rats and mice (Schwartz, 1979). Sanghvi and Gershon (1977) have suggested a link between the actions of the opiates and the relationship of cyclic nucleotides to movements of Ca2+ through membranes. Whereas the formation of cyclic GMP is postulated to be dephysical dependent on Ca’+, antinociception, pendence and tolerance to morphine seem to be related specifically to the uptake of Ca2+ by membranes. The effects on H, receptors may be coupled to translocation of Ca2+ ions (Schwartz, 1979). The stimulation of the accumulation of cyclic AMP in slices of hippocampus mediated by H, receptors is strongly dependent on the external concentration of Ca2+, whereas that mediated by the H, receptor is not. In addition, the formation of cyclic GMP is markedly dependent on external Ca2+ and is selectively mediated by H, receptors. As mentioned earlier, tripelennamine may augment the release of cyclic GMP, which could then act as a central analgesic agent. Although the exact nature of the mechanism is still obscure, the interaction between opiates and H, blockers to produce antinociception and the ability of each to produce antinociception alone seems to be largely dependent upon the actions of cyclic nucleotides and Ca*+ on membranes. In conclusion, the present studies demonstrate that pyrilamine, dephenhydramine, methdilazine, cyclizine and chlorpheniramine, like tripelennamine are capable of producing antinociception as well as enhancing antinociception induced by morphine. The present authors have now determined that all structurally-representative members of the class of H, blockers undergo this interaction with opiates. This effect may be clinically advantageous in cases requiring strong antinociception as well as restriction of opiate intake. In addition, the finding that this effect occurs also supports the widespread reports of opiate-antihistamine abuse and the need for further investigation and evaluation of the extent and implications of the antinociceptive properties of readilyavailable H, antihistamines. Whether or not a significant addictive potential exists for the combinations remains to be established.
Aufrere M. B. and Anderson L. D. (1980) Analgesic effect of continuous intracerebral infusion of guanosine 3’,5’-monophosphate in the rat. Fedn Proc. Fedn Am. Sots exp. Biol. 39: 760.
Bianchi C. and Chini F. J. (1954) Experimental observations on Haffner’s method for testing analgesic drugs. Br. J. Pharmac. 9: 280.
Cohn M. L., Cohn M. and Taylor F. H. (1978) Guanosine 3’,5’-monophosphate: A central nervous system regulator of analgesia. Science 199: 319-322. Foreman J. C., Mongar J. L., Gomperts B. D. and Garland L. G. (1974) A possible role for cvclic AMP in the
regulation of histamine secretion and the action of cromoglycate. Biochem. Pharmac. 24: 538-540. Haffner F. (1929) Experimentalle Prufung schmerzfallen der Mittel. Dt. med. Wschr. 55: 731-733. Havdala H. S., Bluhm R., Blumenfeld L., Malmed A., Borison R. L. and Diamond B. I. (1981) Antihistamines and analgesia. Fedn Proc. Fedn Am. Sdcs exp. Biol. 40: 281.
Henwood R. W. and Mazarkiewicz-Kwilecki I. (1977) Effect of histidine on morphine-induced changes in brain histamine. Age. Act. 7: 494-500. Hui F. W., Sun C. L., Tocus E. C. and Hanig J. P. (1980) Enhanced antinociception in mice with pyribenzamine alone and in combination with opiates. Pharmacologisf 22: 302.
Hui F. W., Sun C. L. and Hanig J. P. (1981) Opiate mixed agonist-antagonist (MAA) interactions with morphine (M) and Dvribenzamine (P) on antinociceDtion (ANTI) in r%e. Proceedings of rhe‘E>ghth Internati&zal Cbgress qf Pharmacology, Tokyo, Japan. Hui F. W., Sun C. L., Tocus E. C. and Hanig J. P. (1983) The effect of tripelennamine alone and in combination with opiates to produce antinociception in mice. L(/e Sci. 32: 1531-1538.
Lee J. R. and Fennessy M. R. (1976) Effects of morphine on brain histamine, antinociception and activity in mice. Clin. exp. Pharmac. Physiol. 3: 179-189. Mattila M. J. and Saarnivaara L. (1968) Modification by antihistamine drugs of the morphine analgesia in rabbits. Annls Med. exp. Biol. Fenn. 46: 72-77.
Mazarkiweicz-Kwilecki I. and Henwood R. W. (1976) Alterations in brain endogenous histamine levels in rats after chronic morphine treatment and morphine withdrawal. Age. Act. 6: 402408. Sanghvi I. S. and Gershon S. (1977) Brain calcium and morphine action. Biochem. Pharmac. 26: 1183-l 185. Schwartz J. C. (1979) Minireview: Histamine receptors in brain. Life Sci. 25: 895-912. Showalter C. V. and Moore L. (1978) Abuse of oentazocine and tripelennamine. J. Am. med. Ass. 239: li10-1612. Tagashira E., Kachur J. F. and Dewey W. L. (1982) Enhancement of antinociceptive a&m of pentazocine and morphine by tripelennamine. Pharmacologist 24: 188. Westrick M. L. and Spratto G. R. (1981) The effect of antihistamines on the analgesic response in the morphinetreated rat. Fedn Proc. Fedn Ams. Sots exp. Biol. 40: 282. Wong C. L. and Roberts M. B. (1975) The possible role of brain histamine and H, and H, receptors in the development of morphine tolerance and physical dependence in mice. Age. Act. 5: 47-83. Wong C. L. and Roberts M. B. (1977) The effects of D-histidine on the expression of morphine tolerance and physical dependence in mice. Age. Act. 7: 241-243.
1985
0028-3908/85 $3.00 + 0.00 Pergamon Press Ltd
in Great Britain
EFFECT OF H, BLOCKERS ALONE AND IN COMBINATION WITH MORPHINE TO PRODUCE ANTINOCICEPTION IN MICE C.-L. J. SUN, F. W. HUI* and J. P. HANI@ Division of Drug Biology, Food and Drug Administration, Washington, DC 20204, U.S.A. (Accepted 17 May 1984)
Smnmary-Antinociception was assessed in male CD-l mice by a modification of Haffner’s tail-clamp procedure. The H, blockers, including an ethylenediamine (pyrilamine), an ethanolamine (diphenhydramine), a phenothiazine (methdilazine), a piperazine (cyclizine) and an alkylamine (chlorpheniramine), all produced antinociception when given alone to mice and also caused potentiation when combined with morphine. Key words: antinociception, cyclizine, chlorpheniramine.
The combination for the purposes
morphine,
H, blocker, pyrilamine, diphenhydramine,
of tripelennarnine with paregoric of drug abuse has previously been
reported (Showalter and Moore, 1978), and unpublished narrative (case reports) and testimonial evidence indicates the current use or abuse of other combinations of tripelennamine with “street narcotics” by addicts. A number of investigators (Havdala, Bluhm, Blumenfeld, Malmed, Borison and Diamond, 1981; Hui, Sun, Tocus and Hanig, 1980,1983; Tagashira, Kachur and Dewey, 1982; Westrick and Spratto, 1981) have confirmed the potentiation of the effects of tripelennamine by morphine in the laboratory. Mixtures of tripelennamine and pentazocine were also reported to be misused as a combination known in the “street” as “Ts and Bs” (Showalter and Moore, 1978). Laboratory studies (Hui, Sun and Hanig, 1981) have confirmed a synergism between these two drugs and have demonstrated a synergism between morphine and pentazocine as well as between other mixed agonist-antagonists. The present study sought to confirm the initial finding of antinociception with tripelennamine alone and the potentiation of its effects by morphine and to extend investigations of the phenomenon to representative compounds of the structural classes of histamine H, blockers. This report describes results obtained with combinations of morphine with an ethylenediamine (‘pyrilamine), an ethanolamine (diphenhydramine), a phenothiazine (methdilazine), a piperazine (cyclizine) and an alkylamine (chlorpheniramine).
*Visiting Scientist, Fogarty International Center, National Institutes of Health, Bethesda, MD 20205, U.S.A. tTo whom requests for reprints should be sent.
methdilazine,
METHODS
Male mice of the CD-l strain (Charles River), weighing approx. 20 g and having free access to food and water, were used in all experiments. Each treatment group consisted of 9-14 mice. The drugs were dissolved in saline and injected subcutaneously in the medio-dorsal lumbar region of the back, with control animals receiving saline. Solutions of drug or saline were injected in a volume of 0.1 ml/10 g of body weight. Antinociception was determined by a modification of the tail-clamp method of Haffner (1929), which was validated (Bianchi and Chini, 1954) following a prescreening procedure for the threshold of pain of each animal. All screened mice were grouped according to their tail-clamp reaction times (fierce biting or striking at the noxious stimulus), which ranged from 1 to 8 sec. The screened mice were then redistributed evenly (the same number of mice at each reaction time) to each treatment group, thereby reducing the effect of the observed variation in reaction time; statistical analysis has demonstrated that this redistribution reduces the background scatter with a tighter fit of the data (small differences can be shown to be significant). The reaction time after placement of the tail-clamp at the mid-tail position was determined as the time which elapsed before the test animal successfully struck or bit the clamp. All testing for antinociception was performed 30min after administration of drug. Most control mice responded within l-5 set, whereas mice which were treated that showed analgesia responded in the 8-30-set range. If a mouse took longer than 60 set to respond, that reaction time was recorded as 60 sec.
C.-L. J. Table
I. Effect of pyrilamine
Treatment None Morphine Pyrilamine Pyrilamine Morphine + pyrilamine Morphine + pyrilamine
SUNe/ al.
on antinociception
Induced
DOS? (mg:kg) .~
Reaction time (see)
II
3.0 5.8 3.9 8.3 9.6 22.3
II 12 II I? II 12
3.0 5.0 15.0 3.0 + 5.0 3.0 + IS.0
by morphine
f 0.5 + 0.4* * 0.3 i o.s* i 0.9*,t.: +2X*,1,:
*Significantly different from value for untreated controls (P i 0.05). tSignificantly different from value for morphine alone (P ~0.05). fSignilicantly different from value for pyrilamine alone at the same dose (P < 0.05).
Morphine was obtained from Dr Arthur Jacobson of the National Institutes of Health. Pyrilamine maleate was supplied by Merck Sharp & Dohme, diphenhydramine by Parke-Davis, methdilazine HCl by Mead Johnson & Co., chlorpheniramine maleate by K & K Laboratories, Inc. and cyclizine HCI by Burroughs Wellcome Co. All values are presented as means +SEM. The differences between treatments and control were analyzed by the unpaired Student’s t-test. Any differences in P value less than 0.05 were considered statistically significant. RESULTS
Pyrilamine, given alone at a dose of 15.0 mg/kg, induced a significant increase in antinociception over the response in untreated controls, whereas the smaller dose of 5.0mg/kg did not (Table 1). When pyrilamine, at the lower dose level, was combined with morphine (3.0mg/kg), the increase in antinociception was approximately the calculated arithmetic sum of the individual effects. In contrast, the combination of morphine with the larger dose of pyrilamine was synergistic.
Table 2. Effect of diohenhvdramine Treatment
~~~~
None Morphine Diphenhydramine Diphenhydramine Morphine + diphenhydramme Morphine + diphenhydramine
As shown in Table 2, antinociception was significantly increased over the value for untreated controls when diphenhydramine was given alone at 15.0 mg/kg but not at 5.0 mg/kg. The combination of either dose with morphine caused a significant increase over values for the groups treated with a single drug, and values for the combined treatment were somewhat greater than the arithmetic sum of the individual values. Methdilazine, given alone at doses of either 2.5 or 5.0mg/kg, caused a significant increase in antinociception over the value for untreated controls (Table 3). When methidilazine, at either of these dose levels, was combined with morphine, antinociception was significantly increased over that obtained with morphine or methdilazine alone. As shown in Table 4, cyclizine given alone at 2.5, 5.0 and 15.0 mg/kg produced antinociception that was significantly greater than the value obtained for untreated controls; however, the dose-response curve appeared to be rather flat, in contrast to that for methdilazine alone (Table 3). The combination of morphine with the two smaller doses of cyclizine produced antinociception that was significantly greater than values for untreated controls or the
on antinociceotion Dose (mg/kg)
3.0 5.0 15.0 3.0 + 5.0 3.0+ 15.0
induced
bv morohine
Reaction time (set)
n
3.3 8.0 4.6 8.9 14.1 21.3
I2 I3 I3 I4 13 13
f 0.4 f 1.5: _+0.7 i 1.2* k 1.8*,t,: + 3.6*,7,x
*Significantly different from value for untreated controls (P ~0.05). different from value for morphine alone (P < 0.05). SSignificantly value for diphenhydramine alone at the same dose (P < 0.05). Table 3. Effect of methdilazine Treatment None Morphine Methdilazine Methdilazine Morphine + methdilazine Morphine + methdilazine
on antinociception Dose !mg/kg) 3.0 2.5 5.0 3.0 + 2.5 3.0 + 5.0
tsignificantly different from
induced by morphine Reaction time (see) 4.9 13.3 9.9 18.7 26.6 32.1
f f * * k i
0.7 2.7* 1.5* I .5* 5.6*,t.f: 3.4*,t,f
n II II II II I1 11
‘Significantly different from value for untreated controls (P < 0.05). tsignificantly different from value for morphine alone (P ~0.05). fSignificantly different from value for methdilazine alone at the same dose (P < 0.05).
3
H, blockers and morphine antinociception Table 4. Effect of cyclizine on antinociception Treatment ~.ll--..~. None Morphine Cyclizine Cyclidne Cyclizine Morphine + cyclizine Morphine + cyclizine Morphine + cyclizine
Dose (mgk)
induced by morphine Reaction time (se@ 3.3 f 0.4 12.4 & 2.9* 7.5 i. I .o* 8.4 2 1.4* 10.3 * 1.7* 17.9 * 1.s*,t 15.4 * 1.7*,t 33.5 + 5.7*,$,$
3.0 2.5 5.0 15.0 3.0 + 2.5 3.0 + 5.0 3.0 + 15.0
n ^~ Ii 10 10 10 10 t: 10
*Significantly different from value from untreated controls (P < 0.05). Wignificantly different from value for cyctizine alone at the same dose (P c 0.05). $Significantly different from value for morphine alone (P < 0.05).
groups given cyclizine alone, but was not significantly different from the value for the group given morphine alone, The combination of morphine with the large dose of cyclizine, however, produced a significant potentiation of antinociception. Chlo~heniramine, given alone at 15.0 mg/kg, caused a significant increase in antinoci~ption (Table 5); at the smaller dose of 5.0 mgjkg, antinociception was slightly greater than that in untreated controls but the increase was not statistically significant. The combination of morphine with the smaller dose of chlo~heniramine produced an additive effect that almost equalled the arithmetic sum of the component responses; however, the combination of morphine with the large dose of chlorpheniramine produced potentiation.
It has been demonstrated previously that tripelennamine alone, at a dose as small as 1.5 mg/kg, caused antinociception in mice (Hui et cd., 1980), and that non-effective doses of nalbuphene (2.0 mg/kg) administered together with noneffective doses of tripelennamine (OS mg/kg) produced significant analgesia in the test system. This finding was in contrast to an earlier published report (Mattila and Saarnivaara, 1968) indicating that cinnarizine, another H, blocker, reduced antinociception induced by morphine in the rabbit. The present authors also found that administration of t~~lennamine (15 mgjkg) together with morphine (2.0 mg/kg) produced an analgesic effect equal to that obtained with 8.0mg of mo~hine~kg alone (Hui et al., 1983). The present study with pyrilamine, di~henhydramine~ meth-
Table 5. Effect of chiorpheniramine Treatment _“.~_~“~_--~~~~~~ None Morphine Chlorphe~~~e Chlorpheniramine Morphine f chlo~heniramine Morphine f chlo~henir~ine
dilazine, cyclizine and chlopheniramine extends the earlier finding to include all of the representative structural classes of histamine H, blockers; e.g. antinociception was obtained when these compounds were administered alone and was potentiated when they were given in combination with morphine. These results lend credence to the extensive anecdotal reports of abuse of a variety of antihista~nes, both alone and in combination with opiates. Although a pha~acolo~cal basis has been established in animals for opiate-like activity, with respect to antinociception, for I-I, antagonists as a class, the mechanism for this action is not resolved. tee and Fennessy (1976) and Mazarkiewicz-Kwilecki and Henwood (1976) studied the relationship between narcotic addiction and histamine and showed that rats, given morphine chronically, had a significant decrease of this amine in the CNS. This depletion could be normalized by daily administration of L-histidine to the animals treated with morphine (Henwood and Mazarkiewicz-Kwil~ki, 1977). In other studies (Wong and Roberts, 1975, 1977), CNS receptors for histamine in the mouse were shown to be involved in the development of tolerance to and physical dependence on morphine. It could be speculated, at this point, that blocking the H, receptor in the CNS to produce or potentiate antinociception may be somewhat equivalent to the normal depletion of the endogenous histamine that appears to occur with the administration of morphine. Augmented antinociception induced by opiates via the histaminergic system may also be related to effects upon cyclic nucleotides and the Cazc uptake system. Foreman, Mongar, Gomperts and Garland (1974) proposed that intra~ilular cyclic AMP regulates the
on antinociception
Dose imgik) 3.0 5.0 15.0 3.0 + 5.0 3.0 + 15.0
_.
induced by morphine
Reaction time W) 5.5 f 0.6 9.5 * 1.2* 7.8 + 1.5 11.5+ 1.7” 16.3 + 3.4*,t 23.4 f 2.8*,t,f
n 11 10 11 IO 9 9
*Significantly different from value for untreated controls (P < 0.05). ~Significantly different from value for chlorpheniramine alone at the same dose (P ~0.05). fdigniticantly different from value for morphine alone (P -=z 0.05).
4
C-L. J. SUN et al. REFERENCES
Ca*+ gating mechanism
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