Agents and Actions, vol. 33, 1/2 (1991)
0065-4299/91/020020-03 $1.50+0.20/0 9 1991 Birkh/iuserVerlag, Basel
Histamine release induced by opioid analgesics: A comparative study using porcine mast cells M. Ennis 1, C. Schneider, E. Nehring and W. Lorenz Institute for Theoretical Surgery, Clinic of the Philipps UniversityMarburg, BaldingerstraBe,W-3550 Marburg
Abstract
Studies in vitro have demonstrated histamine release induced by opioid analgesics from rat peritoneal mast cells and human skin mast cells. In humans, elevated plasma histamine levels have also been found following intravenous or oral administration. This study compared the reactivity of five opioid analgesics on mast cell suspensions obtained from porcine heart, kidneys, liver and lungs. The five compounds investigated were hydromorphone, levomethadone, morphine, pethidine and oxycodone. Both morphine and hydromorphone produced little histamine release from all cell types tested. The other drugs demonstrated clear differences between the different cell populations. Thus, the cardiac cells responded most strongly to oxycodone but were the least responsive to pethidine. These differences, if confirmed in vivo, could indicate which drugs may be more suitable for patients with different underlying disease states.
Introduction
Opioid analgesics are commonly used in anaesthesia and for pain relief. In common with other drugs used in anaesthesia and surgery, these agents cause adverse allergic/pseudoallergic reactions. A number of studies have demonstrated elevated plasma histamine levels following i.v., oral and epidurally applied morphine [1 - 3]. However, these investigations are unable to demonstrate which populatiorls of mast cells are especially sensitive to opioid analgesics. Studies in vitro have concentrated on mast cells derived from the peritoneal cavity of the rat and human skin [4, 5]. Due to the marked heterogeneity of mast cells from different sites, and the usefulness of in vivo and in vitro comparisons, we 1 Present address and address for correspondence: Department of ChemicalPathology,Instituteof Clinical Science,The Queen's University of Belfast,GrosvenorRoad, BelfastBT12 6BA, UK.
have developed methods for the isolation of mast cell containing suspensions from different organs of the pig. The histamine release induced by five opioid analgesics has been compared using mast cells derived from porcine heart, kidney, liver and lungs. Materials and methods Materials
The opioid analgesics were used as their chemically pure salts and were generous gifts from the pharmaceutical companies indicated in brackets: hydromorphone (Knoll A.G., Ludwigshafen), levomethadone (Hoechst, Frankfurt), morphine (Knoll), pethidine (Hoechst) and oxycodone (Merck, Darmstadt). All other reagents were as described in Ennis [6] and Pearce et al. [7].
21
Agents and Actions, vol. 33, 1/2 (1991)
Animals Young pigs (German Landrace-Pietrain) of either sex, age 7 5 - 8 5 days, bodyweight 1 8 - 2 8 kg were used throughout.
Cell isolation and histamine release experiments The animals were held and killed in accordance with the German animal protection laws. The thorax and abdominal cavities were opened and the organs (heart, kidneys, liver and lungs) were removed rapidly and placed into ice-old Tyrode's solution. Tissues were cut into small pieces and extensively washed in Tyrode's solution. However, the liver slices were washed for 15 rain in EDTATyrode's solution, followed by a 5 min wash in calcium and magnesium-free Tyrode's solution. All tissues were then chopped automatically into 1 m m 2 pieces. The mast cell suspensions were obtained by collagenase dispersion based on the method described by Ennis [6]. All cells were prewarmed at 37~ for 5 rain and challenged for 10rain (37~ with the opioid analgesics. Histamine was determined in both supernatants and cell pellets using an automated procedure (Technicon Autoanalyser). All results are expressed as the percent histamine release and given as means _+SEM for the number of experiments noted. The spontaneous histamine release was subtracted in all cases. Results
H y d r o m o r p h o n e and morphine released little histamine from all cell populations tested even at concentrations o f 10 - 2 M. Cardiac mast cells were the most responsive to these agents (Table 1). The oth-
er opioid analgesics tested caused significant histamine release from all o f the cells investigated, with the exception of oxycodone and kidney cells (Table 1). Levomethadone caused histamine release ( > 1 0 % ) at concentrations above 10 -3 M. The pulmonary cells were the most responsive, releasing ca. 60% of their total histamine at 1.5 x 10 . 3 M, whereas the other cell populations released ca. 30%. At the highest concentration tested (5 x 10 3 M) the pulmonary cells were also the most sensitive, followed by the cells derived from porcine liver (Table 1). Although cardiac cells were the first to respond to pethidine (ca. 10% release at 2.5 x 10-3 M), at higher concentrations pulmonary and liver cells were the most responsive (Table 1). Cardiac cells released the most histamine following challenge with oxycodone. However, the maximum release was only ca. 19% (Table 1).
Discussion
The data presented in this paper confirm and extend the data on histamine release induced by opioid analgesics. Although morphine and hydrom o r p h o n e released little histamine from porcine cells, in our hands they caused histamine release from rat peritoneal mast cells as previously demonstrated by G r o s m a n [4] and some release from rat pulmonary cells (Ennis et al., unpublished data). The concentrations of the opioids examined are indeed high. However, after intramuscular administration for example, these concentrations are reached. Furthermore, when applied during anaesthesia, these agents are often given repeatedly and in combination with other agents. The interactions between the many drugs used in anaesthesia, leading to a possible potentiation of histamine release
Table 1
Histamine release (%) induced by opioid analgesics from porcine mast cells. Drug
Hydromorphone (10-2M) Levomethadone (5x 10 3M) Morphine (10-2M) Pethidine (10-2M) Oxycodone (10-2M)
Histamine release (%) from mast cells from: Heart
Kidney
Liver
Lung
8.4_+/.4 (5) 59.9+3.0 (5) 5.3-+1.6 (5) 22.2+2.8 (6) 19.2-+1.4 (6)
5.0_+0.9 (5) 57.9+3.4 (5) 3.0-+0.8 (4) 30.6__+2.2 (5) 6.2__0.6 (5)
3.4_+1.0 (5) 67.9_+3.9 (6) 3.6_+1.3 (5) 46.1_+3.5 (6) 11.0_+2.3 (6)
3.6_+0.6 (4) 79.7+0.5 (4) 1.2_+0.6 (5) 51.3+2.2 (5) 11.2+0.7 (5)
All values are given as means+ SEM for the numberof experiments(n) shownin brackets. The spontaneoushistaminerelease (5-12%) has been subtracted in all cases.
22 responses, has n o t been studied extensively. H o w ever, o u r d a t a f r o m e x p e r i m e n t s w i t h rat perit o n e a l cells suggest that such i n t e r a c t i o n s d o o c c u r [8]. T h u s e v e n agents w h i c h p r o d u c e m i l d hist a m i n e release w h e n given a l o n e m a y be d a n g e r o u s in c o m b i n a t i o n w i t h o t h e r drugs. I n this investigation, the cells f r o m the different tissues were always isolated f r o m the s a m e animal. Thus, the differences in responses were due to m a s t cell h e t e r o g e n e i t y a n d n o t due to a n i m a l variability. T h e differences, if c o n f i r m e d in vivo, c o u l d indicate w h i c h drugs m a y be m o r e suitable for patients w i t h different u n d e r l y i n g disease states.
Acknowledgements This work was supported by a grant from the Deutsche Forschungsgemeinschaft (Lo 199/14-3). The authors wish to thank Mrs Angelika Muth for her excellent technical assistance.
References [1] H. Suttmann, A. Doenicke, W. Lorenz, M. Ennis, O A. Mfiller, R. Dorow and M. Ackenheit, Is perioperative stress a
Agents and Actions, vql. 33, 1/2 (1991) real surgical phenomenon or merely a drug-induced effect? A study comparing the actions of nalbuphine and morphine on subjective factors and endocrinological parameters in volunteers. Theor. Surg. 1, 119-135 (1986).
[2] D. M. Philbin, J. Moss, C. E. Roscow, C. W. Akins and J. L. Rosenberger, Histamine release with intravenous narcotics: Protective effects of H 1 and H2-receptor antagonists. Klin. Wochenschr. 60, 1056-1059 (1982). [3] S. Berg-Seiter, B. Kossmann, W. Dick and W. Lorenz, Untersuchungen zum Verhalten der Plasmahistaminspiegel nach periduraler Morphinapplikation. Anaesthesist 34, 388-391
(1985). [4] N. Grosman, Histamine release from isolated rat mast cells: effect of morphine and related drugs and their interaction with compound 48/80. Agents and Actions 11, 196-203 (1981). [5] R. C. Benyon, The human skin mast cell. Clin. Exp. Allergy 19,
375-387 (1989). [6] M. Ennis, Histamine release from human pulmonary mast cells. Agents and Actions 12, 60-63 (1982). [7] E L. Pearce, M. Ennis, A. Truneh and J. R. White, Role of intra- and extracellular calcium in histamine release from rat peritoneal mast cells. Agents and Actions 11, 51-54 (1981). [8] M. Ennis, Vr Lorenz and W. Gertand, Modulation of histamine release from rat peritoneal mast cells by non-eytotoxie concentrations of the detergents Cremophor El | (oxethylated castor oil) and Triton XIO0. A possible explanation for unexpected adverse drug reactions? Agents and Actions 18, 235-238
(1986).
0065-4299/91/020020-03 $1.50+0.20/0 9 1991 Birkh/iuserVerlag, Basel
Histamine release induced by opioid analgesics: A comparative study using porcine mast cells M. Ennis 1, C. Schneider, E. Nehring and W. Lorenz Institute for Theoretical Surgery, Clinic of the Philipps UniversityMarburg, BaldingerstraBe,W-3550 Marburg
Abstract
Studies in vitro have demonstrated histamine release induced by opioid analgesics from rat peritoneal mast cells and human skin mast cells. In humans, elevated plasma histamine levels have also been found following intravenous or oral administration. This study compared the reactivity of five opioid analgesics on mast cell suspensions obtained from porcine heart, kidneys, liver and lungs. The five compounds investigated were hydromorphone, levomethadone, morphine, pethidine and oxycodone. Both morphine and hydromorphone produced little histamine release from all cell types tested. The other drugs demonstrated clear differences between the different cell populations. Thus, the cardiac cells responded most strongly to oxycodone but were the least responsive to pethidine. These differences, if confirmed in vivo, could indicate which drugs may be more suitable for patients with different underlying disease states.
Introduction
Opioid analgesics are commonly used in anaesthesia and for pain relief. In common with other drugs used in anaesthesia and surgery, these agents cause adverse allergic/pseudoallergic reactions. A number of studies have demonstrated elevated plasma histamine levels following i.v., oral and epidurally applied morphine [1 - 3]. However, these investigations are unable to demonstrate which populatiorls of mast cells are especially sensitive to opioid analgesics. Studies in vitro have concentrated on mast cells derived from the peritoneal cavity of the rat and human skin [4, 5]. Due to the marked heterogeneity of mast cells from different sites, and the usefulness of in vivo and in vitro comparisons, we 1 Present address and address for correspondence: Department of ChemicalPathology,Instituteof Clinical Science,The Queen's University of Belfast,GrosvenorRoad, BelfastBT12 6BA, UK.
have developed methods for the isolation of mast cell containing suspensions from different organs of the pig. The histamine release induced by five opioid analgesics has been compared using mast cells derived from porcine heart, kidney, liver and lungs. Materials and methods Materials
The opioid analgesics were used as their chemically pure salts and were generous gifts from the pharmaceutical companies indicated in brackets: hydromorphone (Knoll A.G., Ludwigshafen), levomethadone (Hoechst, Frankfurt), morphine (Knoll), pethidine (Hoechst) and oxycodone (Merck, Darmstadt). All other reagents were as described in Ennis [6] and Pearce et al. [7].
21
Agents and Actions, vol. 33, 1/2 (1991)
Animals Young pigs (German Landrace-Pietrain) of either sex, age 7 5 - 8 5 days, bodyweight 1 8 - 2 8 kg were used throughout.
Cell isolation and histamine release experiments The animals were held and killed in accordance with the German animal protection laws. The thorax and abdominal cavities were opened and the organs (heart, kidneys, liver and lungs) were removed rapidly and placed into ice-old Tyrode's solution. Tissues were cut into small pieces and extensively washed in Tyrode's solution. However, the liver slices were washed for 15 rain in EDTATyrode's solution, followed by a 5 min wash in calcium and magnesium-free Tyrode's solution. All tissues were then chopped automatically into 1 m m 2 pieces. The mast cell suspensions were obtained by collagenase dispersion based on the method described by Ennis [6]. All cells were prewarmed at 37~ for 5 rain and challenged for 10rain (37~ with the opioid analgesics. Histamine was determined in both supernatants and cell pellets using an automated procedure (Technicon Autoanalyser). All results are expressed as the percent histamine release and given as means _+SEM for the number of experiments noted. The spontaneous histamine release was subtracted in all cases. Results
H y d r o m o r p h o n e and morphine released little histamine from all cell populations tested even at concentrations o f 10 - 2 M. Cardiac mast cells were the most responsive to these agents (Table 1). The oth-
er opioid analgesics tested caused significant histamine release from all o f the cells investigated, with the exception of oxycodone and kidney cells (Table 1). Levomethadone caused histamine release ( > 1 0 % ) at concentrations above 10 -3 M. The pulmonary cells were the most responsive, releasing ca. 60% of their total histamine at 1.5 x 10 . 3 M, whereas the other cell populations released ca. 30%. At the highest concentration tested (5 x 10 3 M) the pulmonary cells were also the most sensitive, followed by the cells derived from porcine liver (Table 1). Although cardiac cells were the first to respond to pethidine (ca. 10% release at 2.5 x 10-3 M), at higher concentrations pulmonary and liver cells were the most responsive (Table 1). Cardiac cells released the most histamine following challenge with oxycodone. However, the maximum release was only ca. 19% (Table 1).
Discussion
The data presented in this paper confirm and extend the data on histamine release induced by opioid analgesics. Although morphine and hydrom o r p h o n e released little histamine from porcine cells, in our hands they caused histamine release from rat peritoneal mast cells as previously demonstrated by G r o s m a n [4] and some release from rat pulmonary cells (Ennis et al., unpublished data). The concentrations of the opioids examined are indeed high. However, after intramuscular administration for example, these concentrations are reached. Furthermore, when applied during anaesthesia, these agents are often given repeatedly and in combination with other agents. The interactions between the many drugs used in anaesthesia, leading to a possible potentiation of histamine release
Table 1
Histamine release (%) induced by opioid analgesics from porcine mast cells. Drug
Hydromorphone (10-2M) Levomethadone (5x 10 3M) Morphine (10-2M) Pethidine (10-2M) Oxycodone (10-2M)
Histamine release (%) from mast cells from: Heart
Kidney
Liver
Lung
8.4_+/.4 (5) 59.9+3.0 (5) 5.3-+1.6 (5) 22.2+2.8 (6) 19.2-+1.4 (6)
5.0_+0.9 (5) 57.9+3.4 (5) 3.0-+0.8 (4) 30.6__+2.2 (5) 6.2__0.6 (5)
3.4_+1.0 (5) 67.9_+3.9 (6) 3.6_+1.3 (5) 46.1_+3.5 (6) 11.0_+2.3 (6)
3.6_+0.6 (4) 79.7+0.5 (4) 1.2_+0.6 (5) 51.3+2.2 (5) 11.2+0.7 (5)
All values are given as means+ SEM for the numberof experiments(n) shownin brackets. The spontaneoushistaminerelease (5-12%) has been subtracted in all cases.
22 responses, has n o t been studied extensively. H o w ever, o u r d a t a f r o m e x p e r i m e n t s w i t h rat perit o n e a l cells suggest that such i n t e r a c t i o n s d o o c c u r [8]. T h u s e v e n agents w h i c h p r o d u c e m i l d hist a m i n e release w h e n given a l o n e m a y be d a n g e r o u s in c o m b i n a t i o n w i t h o t h e r drugs. I n this investigation, the cells f r o m the different tissues were always isolated f r o m the s a m e animal. Thus, the differences in responses were due to m a s t cell h e t e r o g e n e i t y a n d n o t due to a n i m a l variability. T h e differences, if c o n f i r m e d in vivo, c o u l d indicate w h i c h drugs m a y be m o r e suitable for patients w i t h different u n d e r l y i n g disease states.
Acknowledgements This work was supported by a grant from the Deutsche Forschungsgemeinschaft (Lo 199/14-3). The authors wish to thank Mrs Angelika Muth for her excellent technical assistance.
References [1] H. Suttmann, A. Doenicke, W. Lorenz, M. Ennis, O A. Mfiller, R. Dorow and M. Ackenheit, Is perioperative stress a
Agents and Actions, vql. 33, 1/2 (1991) real surgical phenomenon or merely a drug-induced effect? A study comparing the actions of nalbuphine and morphine on subjective factors and endocrinological parameters in volunteers. Theor. Surg. 1, 119-135 (1986).
[2] D. M. Philbin, J. Moss, C. E. Roscow, C. W. Akins and J. L. Rosenberger, Histamine release with intravenous narcotics: Protective effects of H 1 and H2-receptor antagonists. Klin. Wochenschr. 60, 1056-1059 (1982). [3] S. Berg-Seiter, B. Kossmann, W. Dick and W. Lorenz, Untersuchungen zum Verhalten der Plasmahistaminspiegel nach periduraler Morphinapplikation. Anaesthesist 34, 388-391
(1985). [4] N. Grosman, Histamine release from isolated rat mast cells: effect of morphine and related drugs and their interaction with compound 48/80. Agents and Actions 11, 196-203 (1981). [5] R. C. Benyon, The human skin mast cell. Clin. Exp. Allergy 19,
375-387 (1989). [6] M. Ennis, Histamine release from human pulmonary mast cells. Agents and Actions 12, 60-63 (1982). [7] E L. Pearce, M. Ennis, A. Truneh and J. R. White, Role of intra- and extracellular calcium in histamine release from rat peritoneal mast cells. Agents and Actions 11, 51-54 (1981). [8] M. Ennis, Vr Lorenz and W. Gertand, Modulation of histamine release from rat peritoneal mast cells by non-eytotoxie concentrations of the detergents Cremophor El | (oxethylated castor oil) and Triton XIO0. A possible explanation for unexpected adverse drug reactions? Agents and Actions 18, 235-238
(1986).
