- Email: [email protected]
Acupuncture beyond the endorphin concept?
Medical Hypotheses (2002) 58(3), 221±224 & 2002, Elsevier Science Ltd. All rights reserved. doi: 10.1054/mehy.2001.1425, available online at http://www.idealibrary.com on
1
Acupuncture beyond the endorphin concept? I. L. Bonta Emeritus Professor of Pharmacology, Erasmus University Rotterdam, The Netherlands
Summary Traditional acupuncture has been used for treating a variety of health conditions. In contrast, Western physicians limited acupuncture to the alleviation of pain. Concomitant with a recent view that not all kinds of pain are within the reach of acupuncture-induced relief, it has been suggested that some conditions other than pain can be effectively treated by this method. Increased release of the neuropeptide b-endorphin was proposed to explain the antinociceptive function of acupuncture. Even if correct b-endorphin cannot account for the effect of acupuncture in other conditions. Endorphins might be interacting with cytokines, some of which (e.g. interleukin-10) downregulate the inflammatory component of disorders in which acupuncture may be useful. We present a speculative notion of the view that acupuncture may amplify the interaction between neuropeptides and cytokines. A non-invasive approach, such as immune-committed cells harvested from blood of acupuncture-treated patients, could be used to examine this hypothesis. Inclusion of a placebo group might support the credibility of acupuncture. & 2002, Elsevier Science Ltd. All rights reserved.
ANTINOCICEPTION: THE ORTHODOX WESTERN VIEW ON ACUPUNCTURE Acupuncture is among the most ancient therapeutic interventions of mankind. Widespread views date the roots of this procedure as being some 3000 years ago. But it appears that acupuncture must have been practiced at least 5200 years ago (1). On the skin of the oldest European mummified human body, the so-called Tyrolean Iceman, tattoos have been found on the back and legs. The linear geometry of the locations of the points closely corresponds to acupuncture points used to treat arthrosis of the lumbar spine. Computer tomography revealed that this person indeed suffered from this condition. Whether the archaic Central European acupuncturist had any contact (by which means?) with colleagues of the Far East, or was operating independently, is a cultural anthropological issue beyond the scope of this paper. Which Received 9 January 2001 Accepted 25 May 2001 Correspondence to: Ivan L. Bonta, Hanegev 6, 42304 Netanya, Israel. Phone: 972 9 8622205; E-mail: [email protected]
other ailments, besides arthrosis, were the target of the ancient Eurasian acupuncturists is unkown as yet. But in the Far Eastern traditional history of acupuncture, the indication field of this medical art comprises a very wide scale of health conditions, ranging from psychological complaints to ailments which ± at least by modern medical standards ± would need surgical intervention. In contrast, the majority of Western physicians were, until the last two decades or so, reluctant to employ acupuncture for purposes other than the relief of pain. This is understandable because many of the reports which showed beneficial effects of acupuncture outside the antinociceptive influence were the outcome of poorly documented uncontrolled trials, occasionally anecdotical or at best equivocal. The use of acupuncture for pain relief is now unmistakably well documented both in physiological trials on healthy volunteers (2) and in controlled clinical trials on large series of patients (3,4). Also it is clear now that the pain-relieving effect of acupuncture is a specific one, not towards random pain of indiscriminate origin. In support of this is a recent paper which indicates that certain kind of pain, e.g. that which accompanies HIV-related
221
222 Bonta
neuropathy, is outside the reach of acupuncture-induced antinociception (5). As for the physiological basis of pain relief by acupuncture, at present it is common knowledge that this effect is largely mediated via increased release of endogenous opioid neuropeptides; the endorphins (6). It was shown that the induction of analgesia by acupuncture is accompanied by increased cerebrospinal fluid (CSF) levels of b-endorphin from the pituitary±hypothalamic region (7). Furthermore, coadministration of the opiate antagonist naloxone annihilates the acupuncture-mediated analgesia. ACUPUNCTURE OTHER THAN FOR PAIN The impressive increase in the use of acupuncture as a therapeutic intervention, even for poorly defined conditions, recently prompted the US National Institute of Health (NIH) to organize a consensus conference on acupuncture (8). The objective was to provide clinicians and patients with a responsible assessment of the use and effectiveness of acupuncture to treat a variety of conditions. Without any pretention for completeness the most important indications (besides pain control) which were positively recommended will be briefly discussed below. There is clear evidence that needle acupuncture is efficacious for adult postoperative and chemotherapyinduced nausea and vomiting, and probably for nausea during pregnancy (9). Significant studies were devoted to bronchial asthma, suggesting that acupuncture decreases the airway resistance in asthmatic patients (10,11). While an immediate short-lasting effect following acupuncture was most evident, a longer-lasting effect was not excluded. Encouraging effects have been reported in musculoskeletal disorders, such as neurological damage (12) and the immunoinflammatory condition rheumatoid arthritis (13). Somewhat ambiguous were the effects in obese patients (14,15). All these are widely different clinical conditions. Still there is one common denominator which binds them together: there is an incomplete account of the endorphin concept itself for the influence of acupuncture alone or as adjunct therapy in these disorders. ENDORPHINS ARE MORE THAN JUST ANALGESIA There is evidence that acupuncture, a manipulation remote from the brain, has an effect on the central nervous system (CNS). Animal experiments have shown that hypothalamic nuclei have a central role in mediating the effect of acupuncture (16). Lesions in the nucleus arcuatus eliminate the analgesic effects of low-, but not of high-frequency electro-acupuncture and increase in the b-endorphin level has been observed in brainstem tissue Medical Hypotheses (2002) 58(3), 221±224
of animals after acupuncture. In addition, other observations have shown that acupuncture has an influence on spinal-cord opioid receptors (17). A study on healthy volunteers suggests that acupuncture may affect the sympathetic system (2), and that this effect is mediated via mechanisms at hypothalamic levels (18). In turn the hypothalamic b-endorphinergic system may be important not only in pain control but also in the regulation of blood pressure and body temperature. Accordingly, acupuncture, via the endorphin system, may have effects on autonomic functions. Another effect of acupuncture, besides the antinociceptive function, includes inhibition of gastric acid secretion (19). Again however, this is mediated via bendorphin. Interestingly, b-endorphin is not the only neuropeptide which is released following acupuncture (19,20). Increased levels of vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and neuropeptide Y (NPY) have been detected in saliva after acupuncture stimulation. The functional importance of VIP, CGRP and NPY is not well understood, but it is unlikely that their role is limited to nociception. This is in favour of mechanisms which may underlie the effects of acupuncture beyond pain control. COUNTER-IRRITATION AND ACUPUNCTURE This is the appropriate place to discuss the time-honored phenomenon of counter-irritation, and compare it with acupuncture. The two issues share not only some of the underlying physiological mechanisms, but also the controversial medical opinions surrounding them. Much information on counter-irritation has been presented at length in a review (21). The process of counter-irritation essentially consists of combating pain and/or inflammation at one site of the organism by irritating a remote site of the same organism. While possibly younger than acupuncture, it still is a very old medical art, which was advocated for the treatment of inflammation and relief of pain. In animal experiments a large variety of chemical irritants have been used to induce the pain-relieving effects of counter-irritation, but in humans chemical irritants were less effective for this purpose than physical irritation. Some analogy between counter-irritation and acupuncture was proposed more than 20 years ago (21). More recently a full paper has discussed parallel physiological aspects of the two procedures (22). As the practice of acupuncture essentially consists of placing needles subcutaneously at certain body sites remote from those at which pain suppression or downregulation of immunoinflammatory processes or eventually some other noxious event occurs, the resemblance to counter-irritation is evident. There are several variants of & 2002, Elsevier Science Ltd. All rights reserved.
Acupuncture beyond the endorphin concept? 223
acupuncture, but even the simplest procedure, when properly exerted, requires local manipulation of the needle until the patient feels the renowned Qi (`chi') sensation (a deep cramp-like feeling). Both manipulation of the needle in situ and electroacupuncture produce local tissue-irritation, and the analogy with counter-irritation is indeed striking. Counter-irritation triggers the local and remote release of humoral factors (21) and so does acupuncture. The release of endorphins is a plausible explanation for the relief of pain, but what factors might be discharged to account for the beneficial effect of acupuncture in bronchial asthma or rheumatoid arthritis? Both these conditions comprise immunoinflammatory components, hence the answer should be sought in some factor which is related to inflammation, more explicitly a mediator of inflammation. The proposal presented here is that this factor is conceivably the cytokines, because some members of this group of mediators are interacting with b-endorphin. CYTOKINES INTERACTION WITH NEUROPEPTIDES Cytokines belong to the mediators of inflammation. More than 50 cytokines have been identified and all of them are peptides. Those cytokines which are implicated in inflammatory and immune conditions are produced mainly from macrophages and lymphocytes. Some cytokines are proinflammatory, but others are antiinflammatory. The interleukins include an important group within the cytokine superfamily (23). The antiinflammatory interleukins comprise interleukine-4 (IL-4) and interleukine-10 (IL-10) and these are considered as mediating the down-regulation of immunoinflammatory conditions (24±27). However, the function of cytokines is not limited to the immune system. It was shown that cytokines can regulate the pituitary release of b-endorphin (28). On the other hand, besides nerve tissue, immune cells are also sources of b-endorphin (29), which directly or indirectly (via the immune cell derived cytokines) may have an influence on inflammation. Neuropeptides other than endorphins have also been shown to stimulate lymphocytes (30,31). In turn, IL-10 downregulates lymphocyte function (23). b-endorphin has recently been shown to participate in the control of local nociception governed by selectins, which are cytokines promoting the adhesion of immune-committed cells (32). Direct interaction between b-endorphin and selectins has not been studied. CAN CYTOKINE INVOLVEMENT IN ACUPUNCTURE BE TESTED? Provided that neuropeptides and cytokines mutually interact with each other's release and function, this could & 2002, Elsevier Science Ltd. All rights reserved.
form the basis for the speculative notion that acupuncture may amplify this interaction. In turn, such a conceivable physiological process could account for the effect of acupuncture in immunoinflammatory conditions such as bronchial asthma and rheumatoid arthritis. However, any hypothesis awaits to be tested. With experiments in which humans are involved non-invasive approaches are preferred. For testing the present hypothesis, immune-committed cells, such as T-lymphocytes or monocytes, ex vivo harvested from the blood of acupunctured patients could be used. Acupuncture is anyway known to result in an increase in blood white cell count (33). Accordingly no difficulties could be expected for obtaining sufficient number of cells to test the proposal.
PLACEBO EFFECT: A CRUCIAL MATTER Regarding a trial design for testing an acupuncture-related problem, there is the matter of an appropriate control group. In this context the point is not that acupuncture does not work in a number of situations. Certainly it does. But it has to be kept in mind that there is a placebo component which must not be underestimated. Indeed it has been argued that placebo effects are potent to such extent that they can mimic not only the acupunctureinduced antinociception, but also other effects of acupuncture such as inhibition of gastric acid secretion (34). In this context it has been suggested that acupuncture is possibly a uniquely effective method in the activation of positive placebo effects (18). The effects of placebos may reflect the capacity of an individual to recruit the endogenous opiate peptide system (35). Accordingly, endorphins may be released in response to placebos. In view of the interaction between endorphins and cytokines (28,29), there is no reason to disbelieve that release of cytokines could occur during placebo-mediated effects of acupuncture. In order that these events be calculable, a placebo method of needling ± with the same psychological impact, including the Qi sensation ± as actual needling is required. A placebo needle which meets the above criteria has recently been developed (36) and should be included in a trial as proposed. Such studies might not only serve to support the credibility of acupuncture, but also to uncover additional areas where this procedure might be of benefit.
ACKNOWLEDGEMENTS Amos D. Korczyn (Professor of Neurology, Sourasky Medical Center and Sackler Medical School, Tel Aviv University, Israel) contributed to the placebo section of this paper. JoeÈl Rak (Professor of Anatomy and Anthropology, Tel Aviv University), who is a disbeliever of acupunture's efficiency, was kind enough to read and discuss the paper. Medical Hypotheses (2002) 58(3), 221±224
224 Bonta
REFERENCES 1. Dorfer L., Moser M., Spindler K., Bahr., Egart-Vigl E., Dohr G. 5200-year-old acupuncture in central Europe? Science 1998; 282: 242±243. 2. Knardahl S., Elam M., Olausson B., Wallin B. G. Sympathetic nerve activity after acupuncture in humans. Pain 1998; 75: 19±25. 3. Marwick C. Acceptance of some acupuncture applications. JAMA 1997; 278: 1725±1727. 4. Hsu D. T., Diehl D. L. The West gets the point. Lancet 1998; 352: SIV 1. 5. Shlay J. C., Chaloner K., Max M. B. et al. Acupuncture and amitryptilene for pain due to HIV-related peripheral neuropathy. JAMA 1998; 280: 1590±1595. 6. HoÈkfelt T. Neuropeptides in perspective: the last ten years. Neuron 1991; 7: 867±879. 7. SjoÈlund B., Terenius L., Erickson M. Increased cerebrospinal fluid levels of endorphins after electro-acupuncture. Acta Physiol Scand 1977; 100: 382±384. 8. Acupuncture ± NIH Consensus Conference. JAMA 1998; 280: 1518±1524. 9. Dundee J. W., McMillan C. Positive evidence for P6 acupuncture antiemesis. Postgrad Med J 1991; 67: 47±52. 10. Jobst K., Chen J. H., McPherson K. Controlled trial of acupuncture for disabling breathlessness. Lancet 1986; 20(27): 416±418. 11. Tandon M., Philip F. T. Comparison of real and placebo acupuncture in histamine-induced asthma. A double-blind crossover study. Chest 1989; 96: 102±105. 12. Longworth W., McCarthy P. W. Review of research on acupuncture for the treatment of lumbar disk protrusions and associated neurological symptomatology. J Altern Complement Med 1997; 3: 55±76. 13. David J., Townsend S., Sathanathan R., Kriso S., Dore C. J. Effect of acupuncture on patients with rheumatoid arthritis: a randomized placebo-controlled cross-over study. Rheumatology (Oxford) 1999; 38: 864±869. 14. Mok M. S. Treatment of obesity by acupuncture. Am J Clin Nutr 1976; 29: 832±835. 15. Richards D., Morley J. Stimulation of auricular acupuncture points in weight loss. Aust Fam Physician 1998; 27(Suppl 2): S73±77. 16. Wang Q., Mao L., Han J. Great nucleus of hypothalamus mediates low but not high frequency electroacupuncture analgesia in rats. Brain Res 1990; 9: 60±66. 17. Chen X. H., Han J. S. All three types of opioid receptors in the spinal cord are important for 2/15 Hz electroacupuncture analgesia. Eur J Pharmacol 1992; 211: 203±210. 18. Andersson S., Lundberg T. Acupuncture ± from empiricism to science: functional background to acupuncture effects in pain and disease. Med Hypotheses 1995; 45: 271±281. 19. Jin H. O., Zhou L., Lee K. Y., Chang T. M., Chey W. Y. Inhibition of acid secretion by electrical acupuncture is mediated via b-endorphin and somatostatin. Am J Physiol 1996; 271: G524±G530.
Medical Hypotheses (2002) 58(3), 221±224
20. Dawidson I., Angmar-MaÃnsson B., Blom M., Theodorsson E., Lundeberg T. The influence of sensory stimulation (acupuncture) on the release of neuropeptides in the saliva of healthy subjects. Life Sci 1998; 63: 659±674. 21. Bonta I. L. Endogenous Modulators of the Inflammatory Response. In: Vane J. R., Ferreira S. H., eds. Handbook of Experimental Pharmacology, Vol. 50/I. Berlin, Heidelberg: Springer Verlag, 1978: 533±534. 22. Le Bars D., Willer J. C., De Broucker T., Villanueva L. Neurophysiological mechanisms involved in the pain relieving effects of counterirritation and related techniques including acupuncture. In: Stux G., Pomeranz B., eds. Scientific Bases of Acupuncture. Heidelberg, Berlin: Springer, 1989: 79±112. 23. Rang H. P., Dale M. M., Ritter J. M. Pharmacology: Cytokines, 4th Edn. Edinburgh: Churchill Livingstone, 1999: 224±226. 24. Sundstedt A., HoÈiden I., Rosendahl A., Kalland T., v.Rooijen N., Dohlsten M. Immunoregulatory role of IL-10 during superantigen-induced hyporesponsiveness in vivo. J Immunol 1997; 158: 180±186. 25. Cohen S. B., Parry S. L., Feldmann M., Foxwell B. Autocrine and paracrine regulation of human T cell IL-10 production. J Immunol 1997; 158: 5596±602. 26. Pretolani M., Goldman M. Interleukin-10: a potential therapy for allergic inflammation? Immunol Today 1997; 18: 277±280. 27. Niiro H., Otsuka T., Izuhara K. et al. Regulation by interleukin-10 and interleukin-4 of cyclooxygenase-2 expression in human neutrophils. Blood 1997; 89: 1621±1628 28. Van der Meer M. J., Hermans A. R., Pesman G. J., Sweep C. G. Effect of cytokines on pituitary beta-endorphin and adrenal corticosterone release in vitro. Cytokine 1996; 8: 238±247. 29. Cabot P. J., Carter L., Gaiddon C. et al. Immune cell-derived betaendorphin: Production, release and control of inflammatory pain in rats. J Clin Invest 1997; 100: 142±148. 30. Faith E. R., Liang H. J., Murgo A. J., Plotnikoff N. P. Neuroimmunomodulation with encephalins: enhancement of human natural killer (NK) cell activity in vitro. Clin Immunol Immunopath 1984; 31: 412±418. 31. Neil K., Allen J., Morley J. E. Enkephalins stimulate normal human peripheral blood lymphocyte natural killer activity. Life Sci 1984; 35: 53±59. 32. Machelska H., Cabot P. I., Mousa S. A., Zhang Q., Stein C. Pain control in inflammation governed by selectins. Nature Med 1998; 4: 1425±1428. 33. Brown M. L., Ulett G. A., Stern J. A. The effects of acupuncture on white cell counts. Am J Clin Med 1974; 2: 383±398. 34. Treves Th., Korczyn A. D. Letter to the Editor. Pain 1980; 9: 121. 35. Rosenblatt M. The endogenous opiate peptides. In: Braunwald M., ed. Harrison's Principles of Internal Medicine, 11th Edn. New York: McGraw Hill, 1987: 381. 36. Streitberger K., Kleinhenz J. Introducing a placebo needle into acupuncture research. Lancet 1998; 352: 364±365.
& 2002, Elsevier Science Ltd. All rights reserved.
1
Acupuncture beyond the endorphin concept? I. L. Bonta Emeritus Professor of Pharmacology, Erasmus University Rotterdam, The Netherlands
Summary Traditional acupuncture has been used for treating a variety of health conditions. In contrast, Western physicians limited acupuncture to the alleviation of pain. Concomitant with a recent view that not all kinds of pain are within the reach of acupuncture-induced relief, it has been suggested that some conditions other than pain can be effectively treated by this method. Increased release of the neuropeptide b-endorphin was proposed to explain the antinociceptive function of acupuncture. Even if correct b-endorphin cannot account for the effect of acupuncture in other conditions. Endorphins might be interacting with cytokines, some of which (e.g. interleukin-10) downregulate the inflammatory component of disorders in which acupuncture may be useful. We present a speculative notion of the view that acupuncture may amplify the interaction between neuropeptides and cytokines. A non-invasive approach, such as immune-committed cells harvested from blood of acupuncture-treated patients, could be used to examine this hypothesis. Inclusion of a placebo group might support the credibility of acupuncture. & 2002, Elsevier Science Ltd. All rights reserved.
ANTINOCICEPTION: THE ORTHODOX WESTERN VIEW ON ACUPUNCTURE Acupuncture is among the most ancient therapeutic interventions of mankind. Widespread views date the roots of this procedure as being some 3000 years ago. But it appears that acupuncture must have been practiced at least 5200 years ago (1). On the skin of the oldest European mummified human body, the so-called Tyrolean Iceman, tattoos have been found on the back and legs. The linear geometry of the locations of the points closely corresponds to acupuncture points used to treat arthrosis of the lumbar spine. Computer tomography revealed that this person indeed suffered from this condition. Whether the archaic Central European acupuncturist had any contact (by which means?) with colleagues of the Far East, or was operating independently, is a cultural anthropological issue beyond the scope of this paper. Which Received 9 January 2001 Accepted 25 May 2001 Correspondence to: Ivan L. Bonta, Hanegev 6, 42304 Netanya, Israel. Phone: 972 9 8622205; E-mail: [email protected]
other ailments, besides arthrosis, were the target of the ancient Eurasian acupuncturists is unkown as yet. But in the Far Eastern traditional history of acupuncture, the indication field of this medical art comprises a very wide scale of health conditions, ranging from psychological complaints to ailments which ± at least by modern medical standards ± would need surgical intervention. In contrast, the majority of Western physicians were, until the last two decades or so, reluctant to employ acupuncture for purposes other than the relief of pain. This is understandable because many of the reports which showed beneficial effects of acupuncture outside the antinociceptive influence were the outcome of poorly documented uncontrolled trials, occasionally anecdotical or at best equivocal. The use of acupuncture for pain relief is now unmistakably well documented both in physiological trials on healthy volunteers (2) and in controlled clinical trials on large series of patients (3,4). Also it is clear now that the pain-relieving effect of acupuncture is a specific one, not towards random pain of indiscriminate origin. In support of this is a recent paper which indicates that certain kind of pain, e.g. that which accompanies HIV-related
221
222 Bonta
neuropathy, is outside the reach of acupuncture-induced antinociception (5). As for the physiological basis of pain relief by acupuncture, at present it is common knowledge that this effect is largely mediated via increased release of endogenous opioid neuropeptides; the endorphins (6). It was shown that the induction of analgesia by acupuncture is accompanied by increased cerebrospinal fluid (CSF) levels of b-endorphin from the pituitary±hypothalamic region (7). Furthermore, coadministration of the opiate antagonist naloxone annihilates the acupuncture-mediated analgesia. ACUPUNCTURE OTHER THAN FOR PAIN The impressive increase in the use of acupuncture as a therapeutic intervention, even for poorly defined conditions, recently prompted the US National Institute of Health (NIH) to organize a consensus conference on acupuncture (8). The objective was to provide clinicians and patients with a responsible assessment of the use and effectiveness of acupuncture to treat a variety of conditions. Without any pretention for completeness the most important indications (besides pain control) which were positively recommended will be briefly discussed below. There is clear evidence that needle acupuncture is efficacious for adult postoperative and chemotherapyinduced nausea and vomiting, and probably for nausea during pregnancy (9). Significant studies were devoted to bronchial asthma, suggesting that acupuncture decreases the airway resistance in asthmatic patients (10,11). While an immediate short-lasting effect following acupuncture was most evident, a longer-lasting effect was not excluded. Encouraging effects have been reported in musculoskeletal disorders, such as neurological damage (12) and the immunoinflammatory condition rheumatoid arthritis (13). Somewhat ambiguous were the effects in obese patients (14,15). All these are widely different clinical conditions. Still there is one common denominator which binds them together: there is an incomplete account of the endorphin concept itself for the influence of acupuncture alone or as adjunct therapy in these disorders. ENDORPHINS ARE MORE THAN JUST ANALGESIA There is evidence that acupuncture, a manipulation remote from the brain, has an effect on the central nervous system (CNS). Animal experiments have shown that hypothalamic nuclei have a central role in mediating the effect of acupuncture (16). Lesions in the nucleus arcuatus eliminate the analgesic effects of low-, but not of high-frequency electro-acupuncture and increase in the b-endorphin level has been observed in brainstem tissue Medical Hypotheses (2002) 58(3), 221±224
of animals after acupuncture. In addition, other observations have shown that acupuncture has an influence on spinal-cord opioid receptors (17). A study on healthy volunteers suggests that acupuncture may affect the sympathetic system (2), and that this effect is mediated via mechanisms at hypothalamic levels (18). In turn the hypothalamic b-endorphinergic system may be important not only in pain control but also in the regulation of blood pressure and body temperature. Accordingly, acupuncture, via the endorphin system, may have effects on autonomic functions. Another effect of acupuncture, besides the antinociceptive function, includes inhibition of gastric acid secretion (19). Again however, this is mediated via bendorphin. Interestingly, b-endorphin is not the only neuropeptide which is released following acupuncture (19,20). Increased levels of vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and neuropeptide Y (NPY) have been detected in saliva after acupuncture stimulation. The functional importance of VIP, CGRP and NPY is not well understood, but it is unlikely that their role is limited to nociception. This is in favour of mechanisms which may underlie the effects of acupuncture beyond pain control. COUNTER-IRRITATION AND ACUPUNCTURE This is the appropriate place to discuss the time-honored phenomenon of counter-irritation, and compare it with acupuncture. The two issues share not only some of the underlying physiological mechanisms, but also the controversial medical opinions surrounding them. Much information on counter-irritation has been presented at length in a review (21). The process of counter-irritation essentially consists of combating pain and/or inflammation at one site of the organism by irritating a remote site of the same organism. While possibly younger than acupuncture, it still is a very old medical art, which was advocated for the treatment of inflammation and relief of pain. In animal experiments a large variety of chemical irritants have been used to induce the pain-relieving effects of counter-irritation, but in humans chemical irritants were less effective for this purpose than physical irritation. Some analogy between counter-irritation and acupuncture was proposed more than 20 years ago (21). More recently a full paper has discussed parallel physiological aspects of the two procedures (22). As the practice of acupuncture essentially consists of placing needles subcutaneously at certain body sites remote from those at which pain suppression or downregulation of immunoinflammatory processes or eventually some other noxious event occurs, the resemblance to counter-irritation is evident. There are several variants of & 2002, Elsevier Science Ltd. All rights reserved.
Acupuncture beyond the endorphin concept? 223
acupuncture, but even the simplest procedure, when properly exerted, requires local manipulation of the needle until the patient feels the renowned Qi (`chi') sensation (a deep cramp-like feeling). Both manipulation of the needle in situ and electroacupuncture produce local tissue-irritation, and the analogy with counter-irritation is indeed striking. Counter-irritation triggers the local and remote release of humoral factors (21) and so does acupuncture. The release of endorphins is a plausible explanation for the relief of pain, but what factors might be discharged to account for the beneficial effect of acupuncture in bronchial asthma or rheumatoid arthritis? Both these conditions comprise immunoinflammatory components, hence the answer should be sought in some factor which is related to inflammation, more explicitly a mediator of inflammation. The proposal presented here is that this factor is conceivably the cytokines, because some members of this group of mediators are interacting with b-endorphin. CYTOKINES INTERACTION WITH NEUROPEPTIDES Cytokines belong to the mediators of inflammation. More than 50 cytokines have been identified and all of them are peptides. Those cytokines which are implicated in inflammatory and immune conditions are produced mainly from macrophages and lymphocytes. Some cytokines are proinflammatory, but others are antiinflammatory. The interleukins include an important group within the cytokine superfamily (23). The antiinflammatory interleukins comprise interleukine-4 (IL-4) and interleukine-10 (IL-10) and these are considered as mediating the down-regulation of immunoinflammatory conditions (24±27). However, the function of cytokines is not limited to the immune system. It was shown that cytokines can regulate the pituitary release of b-endorphin (28). On the other hand, besides nerve tissue, immune cells are also sources of b-endorphin (29), which directly or indirectly (via the immune cell derived cytokines) may have an influence on inflammation. Neuropeptides other than endorphins have also been shown to stimulate lymphocytes (30,31). In turn, IL-10 downregulates lymphocyte function (23). b-endorphin has recently been shown to participate in the control of local nociception governed by selectins, which are cytokines promoting the adhesion of immune-committed cells (32). Direct interaction between b-endorphin and selectins has not been studied. CAN CYTOKINE INVOLVEMENT IN ACUPUNCTURE BE TESTED? Provided that neuropeptides and cytokines mutually interact with each other's release and function, this could & 2002, Elsevier Science Ltd. All rights reserved.
form the basis for the speculative notion that acupuncture may amplify this interaction. In turn, such a conceivable physiological process could account for the effect of acupuncture in immunoinflammatory conditions such as bronchial asthma and rheumatoid arthritis. However, any hypothesis awaits to be tested. With experiments in which humans are involved non-invasive approaches are preferred. For testing the present hypothesis, immune-committed cells, such as T-lymphocytes or monocytes, ex vivo harvested from the blood of acupunctured patients could be used. Acupuncture is anyway known to result in an increase in blood white cell count (33). Accordingly no difficulties could be expected for obtaining sufficient number of cells to test the proposal.
PLACEBO EFFECT: A CRUCIAL MATTER Regarding a trial design for testing an acupuncture-related problem, there is the matter of an appropriate control group. In this context the point is not that acupuncture does not work in a number of situations. Certainly it does. But it has to be kept in mind that there is a placebo component which must not be underestimated. Indeed it has been argued that placebo effects are potent to such extent that they can mimic not only the acupunctureinduced antinociception, but also other effects of acupuncture such as inhibition of gastric acid secretion (34). In this context it has been suggested that acupuncture is possibly a uniquely effective method in the activation of positive placebo effects (18). The effects of placebos may reflect the capacity of an individual to recruit the endogenous opiate peptide system (35). Accordingly, endorphins may be released in response to placebos. In view of the interaction between endorphins and cytokines (28,29), there is no reason to disbelieve that release of cytokines could occur during placebo-mediated effects of acupuncture. In order that these events be calculable, a placebo method of needling ± with the same psychological impact, including the Qi sensation ± as actual needling is required. A placebo needle which meets the above criteria has recently been developed (36) and should be included in a trial as proposed. Such studies might not only serve to support the credibility of acupuncture, but also to uncover additional areas where this procedure might be of benefit.
ACKNOWLEDGEMENTS Amos D. Korczyn (Professor of Neurology, Sourasky Medical Center and Sackler Medical School, Tel Aviv University, Israel) contributed to the placebo section of this paper. JoeÈl Rak (Professor of Anatomy and Anthropology, Tel Aviv University), who is a disbeliever of acupunture's efficiency, was kind enough to read and discuss the paper. Medical Hypotheses (2002) 58(3), 221±224
224 Bonta
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