Our torments also may in length of time become our elements

71

T I P S - February 1 9 8 3

increased permeability to one or more ions such as CI- or K + (Ref. 13). They cause a stereospecific hyiaerpolarization of the neuronal membrane which entails an increase in membrane conductance. This effect is reversible by the narcotic antagonist naloxone but not by antagonists of other neurotransmitters including a2-antagonists. Tolerance develops to the inhibitory action of opiates on spontaneous firing in the LC, and this results in an increased fh-ing rate during withdrawaP 4. The effects of opiates on behavior usually are the opposite of those produced by electrical stimulation of LC, and opiate abstinence is believed to resemble LC stimulation in many respects. Clonidine also inhibits LC neurons but it does so by stimulating a2-adrenoceptors. As noted above, it does not bind to the opiate binding sites or produce any other direct effect on the opiate-sensitive membrane sites. Its action is inhibited by specific a2-adrenoceptor antagonists, not by naloxone. Clonidine is believed to inhibit LC firing and its action is related to a reduction of norepinephrine release. Our working hypothesis may be stated as follows: during narcotic withdrawal, LC activity is disinhibited as a result of the removal of the inhibitory opiates from their sites of action. As a consequence of this disinhibition, many physiological effects mediated by LC hyperactivity are provoked. Either clonidine or large doses of opiates can reinstate the neuronal inhibition and so alleviate the narcotic withdrawal symptoms. This alleviation of symptoms is the prime objective of clinical management. On the other hand, if administration of opiates is renewed to alleviate withdrawal, the inhibition of the LC will take place as with clonidine but this will also continue to induce tolerance and dependence by the same neuropathological processes which previously compromised the structural integrity and functions of the neurons. The use of opiates would therefore be counterproductive. By contrast, clonidine relieves the symptoms but the opiate-sensitive neurons are not exposed to opiates and are thus spared further deterioration. Instead, the opiate-free environment permits the body's own homeostatic mechanisms to promote healing and gradual recovery of the LC neurons, i.e. return to their normal, healthy state. Much of the above interpretation, however, remains hypothetical and needs to be verified by critically designed experiments. Although most of the evidence available to date stems from LC-related research, we can by no means infer that narcotic addiction is solely a product of the noradrenergic system or that all of the neuropathoiogic changes associated with addiction can he

corrected by clonidlne. In point of fact, narcotic dependence involves many neurotransmitter systems and many of the related alterations are not immediately corrected by clonidine. Dopamine receptor supersensitivity, for example, results from chronic narcotic use, and many of the psychopathological behavior patterns and neuroendocrine changes occurring during withdrawal are directly attributable to dopaminergic supersensitivity1, which clonidine does not counteract. Deficit of prolactin release ~, aggressivity ~6, and the compulsive craving for narcotics are unaffected by administration of clonidine. Reading list 1 LaI, H. (1975)LifeScL 17,483-496 2 Lal, H . Pun, S K and Karkalas, Y (1971) Pharmacologist 13,263 3 Karkalas, J and Lal, H. (1973) Pharmacopsychtat 8. 248-251 4 Hynes, M andLal, H (1981)Drug Dev, Res. 1. 199-209 5 Lal. H. and Shearman, G T. (1981) Prog. Clm and Biol. Res. 71,99-145 6 Shearman, G . T , L a l , H. andUrsfllo, R.C (1980) Pharmacol. Biochem. Behav. 12, 573--575 7 Washton, A. M., Resnick, R B . Perzel, J F. and Garwood, J. (1981) Lancet t, 991-992 8 Lal, H., Shearman, G T and Ursillo, R C (1981)J. Clm. Pharmacol. 21, 16-19 9 Lal, H and Shearman, G (1981) Drug Devel. Res. 1,37-41 10 Fielding, S., Spauldmg, T C and Lal, H. (1981) Prog. Clin. and BioL Res 71,225-242 11 Shearman, G T , Hynes, M. and Lal, H. (1981)

Prog. Chn. and Biol. Res. 71,259-276 12 Bennett, D. A., deFeo, J. J , Elko, E E and Lal, H (1982)Drug Dev. Res. 2, 175--179 13 Pepper, C M. and Henderson, G. (1980)Science 209, 394-396 14 Koef, J , Bunny, B. S. and Aghajanmn, G K. (1974) Eur J. Pharmacol. 25, 165-169 15 Gold, M., Pottach, A., Finn, L., Kleber, H. and Extem, I. (1980)Psychtat. Res. 2, 205-210 16 Glanutsos, G , Hynes. M. O. and Lal, H. (1976) Psychopharm. Comm. 2. 165-171 Dr Smart Fielding received a Ph.D degreefrom the Umversay of Delaware in 1968. In the same year, he took a research position at Ciba-Geigy Pharmaceutical Co. as Manager of Psychopharmacology Research. In 1975, he joined Hoechst-Roassel Pharmaceuticals, lnc., and is currently the Associate Director of Biological Sciences and Manager of Pharmacology. In addaion, he holds an Adjunct Associate Professorship in the Graduate School of Psychology at Fairletgh Dickinson Universay, Madison, New Jersey and an Adlunct Professorship in the Department of Pharmacology at University of Rhode Island, Kingston, Rhode Island. Dr Harbans Lal received a Ph.D. in Pharmacology from the Umversity of Chicago m 1962. Since then, he has held teaching and research posiUons at HT Research Institute, the University of Kansas, University of Rhode Island and Northwestern Universay. He is currently Professor and Chairman of the Department of Pharmacology at Texas College of Osteopatlnc Medicine, Adjunct Professor of Pharmacology, Toxicology, and Psychology at the Umversity of Rhode Island, Professor of Biology at North Texas State UniversUy,Adlunct Professor of Chemistry at the Texas Christian University, and Research Associate at Rhode Island Psychiatric Research and Training Center.

Our t o r m e n t s also m a y in l e n g t h of t i m e b e c o m e our elements* John R. J. Sorenson Department of Biopharmaceuncal Sciences, College of Pharmacy, and Department of Pharmacology, College of Medicine, UniversUyof Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205 U.S.A.

A simple chemical reaction which has not been previously recognized as accounting for the formation of active metabolites of drugs is now providing exciting new developments in pharmacological approaches to treatment of various diseases, which may now be better understood or recognized as inflammatory disease of various tissues. The simple chemical reaction is complexation, the reaction of a metal ion with a complexing agent to form a metal * Milton's Paradise Lost.

complex. Multidentate complexing agents form a class of complexes known as chelates. Since many drugs are chemicals which have complexing reactivity, the formation of metal complexes with essential metalloelements normally found in the body, and required for normal metabolism, should he considered as metabolic transformations. If complexes of these drugs can be shown to be more pharmacologically effective and less toxic than the parent drugs they should be considered as possible

ElsevierBtomedlealPre~ 1983 0165- 6147/83/0000- 0000/$01O0

72 active metabolites of the parent drugs. If it is found or it can be shown that the biochemical lesion causing the disease is a decrease in metal-dependent enzyme activity or that in the normal physiological state the lesion does not result because of a normally functioning metal-dependent enzyme or physiological process, then the pharmacological effect of the complex in the disease state is truly an exciting development. Recognition of the biochemical lesion or the impaired physiological state as the cause of the disease allows a better understanding of the disease. Unfortunately, neither undergraduate nor graduate education in the physical or most biological sciences has prepared us to recognize the significance of these exciting new developments which are centered about essential metaUoelement metabolism. Over 50 years ago - 1928 - it was demonstrated that copper was essential for normal metabolism because it alone corrected the anemia associated with a previously unrecognized disease state, copper deficiency 1. Ten years later in 1938 it was observed that rheumatoid arthritics had a higher than normal serum copper concentration due to an elevation of copper amino acid complexes, a copper albumin complex, and ceruloplasmin, which returned to normal concentrations with remission of this disease2. Thirteen years later in 1941, it was shown by Forestier that two copper complexes were effective in treating a variety of arthritic diseases in man and that they were more effective than all other drugs including gold sodium thiomalate, which Forestier had introduced in 1929 for the treatment of rheumatoid arthritis. The first pharmacological report that copper complexes had anti-inflammatory activity in an animal model of inflammation appeared 22 years after effectiveness had been demonstrated in man a. It is likely that research in this area ceased because there was little, if any, understanding as to why copper complexes had anti-inflammatory or anti-arthritic activity, and with the discovery of hydrocortisone it was thought by many that a 'cure' for rheumatoid arthritis had been found. As a result, the use of copper complexes for the treatment of arthritic diseases did not develop further until it was suggested, in 1974, that copper chelates were the active metabolites of the anti-arthritic

drugs 4. The work that led to the suggestion that copper chelates were the active metabolites of the anti-arthritic drugs began in 1966 with the observation that copper acetate had anti-inflammatory activity and the realization that all anti-arthritic drugs were chelating agents. This led to the hypothesis that

TIPS - February 1983

the formation of copper chelates or com- the inflammatory responses associated with plexes in vivo would account for the brain tumors. The suggestion that copper activities of both the copper 'salt' (copper complexes would be effective as antiacetate) and chelating drugs. When this convulsant agents was supported with the was tested it was found that copper che- observation that they were effective in prelates, synthesized with chelating com- venting seizures in recognized models of pounds that had no anti-inflammatory activ- petit and grand real epilepsy. These obserity of their own, were potent anti- vations suggested that the active metaboinflammatory agents, more potent than lites of the anti-epileptic drugs were also either copper acetate or the chelating com- copper complexes and it was demonstrated pounds. Copper chelates of the clinically that a copper complex of a recognized used anti-arthritic drugs were then anti-convulsant drug was more effective examined and shown to be more potent than than the parent drug. Copper complexes of other anti-epileptic drugs are also being the parent drugs. Pursual of the existing literature led to the examined for their effectiveness as antisuggestion that these copper chelates might convulsants. The literature concerning ceruloplasmin, be facilitating tissue repair processes5. If this were the case then they might also be copper amino acid complexes and copper effective in facilitating repair of tissue in albumin and their role in the acute phase other disease states, which might also be response to microbial infections is clears . recognized as inflammatory diseases. To Leukocyte endogenous mediator (LEM), examine this possibility copper chelates leukocyte activity factor (LAF), endogenwere examined for their ability to prevent ous pyrogen (EP), which appear to be the and treat gastric ulcers. Approximately 80 same substance, are released by leukocytes copper complexes were studied and all of in response to microbial and other insults. them were effective in preventing the Shay They initiate movement of plasma zinc and rat ulcer. A number of them are more effec- iron containing components to the liver tive than existing clinically used anti-ulcer where they are required, in part, for the drugs and copper complexes of the clini- synthesis of the copper-containing compocally used anti-ulcer drugs are more effec- nents of plasma, which increase in response tive than the parent drugs. In addition, cop- to infection and other insults. This acute per complexes were shown to increase gas- phase response is consistent with the obsertric ulcer healing in a surgically-induced vation that copper complexes of antigastric ulcer and they were shown to be bacterial, anti-fungal, and anti-viral agents are more effective than the parent drugs 7. non-ulcerogenic in normal rats. The anti-ulcer activity of copper com- An exciting recent development is that copplexes makes them unique anti- per complexes also have anti-mycoplasmal inflammatory agents since all other anti- activity in vivo and in vitro. These obserinflammatory agents are ulcerogenicL The vations suggest that the beneficial effects of ulcerogenic anti-arthritic drugs were con- antibiotics in the treatment of arthritic disverted to anti-ulcer agents by converting eases may be, in part, due to the formation them to their copper complexes. Itwas also of their copper complexes in vivo. Another recent development which has shown that gastric ulcers caused by an anti-arthritic drug could be prevented with great promise for improving our understanding of the etiology of neoplastic disthe copper complex of the same drug. Copper complexes were also effective in eases is the observation that small molecupreventing ulcers caused by pretreatment lar weight copper complexes decrease with anti-arthritic drugs. Since 1976 there tumor growthin vivo by causing differentihave been over 200 publications that have ation of the neoplastic cells to normal cell confirmed and extended the observations types and increase survival by decreasing metastasis s. Neoplastic cell killing was not that copper complexes have antiobserved. Since neoplastic cells have inflanarnatory and anti-ulcer activitiess. Pursuing the literature concerning cop- decreased superoxide dismutase activity9 per metabolism also revealed that seizures and small molecular weight complexes superoxide dismutase-mimetic are a feature of copper deficiency in ani- have activity1°, studying the anti-neoplastic mals and man s. This observation is consistent with the recognized role of copper- activity of copper complexes may provide greater understanding of neoplastic disease dependent enzymes in the synthesis of putative seizure modulators and disturbances development and enable improved in copper metabolism associated with approaches to therapy. The recognition that superoxide disepilepsy. Epileptic seizures are also known to occur with recognized inflammatory mutase (SOD) activity is decreased in changes in the central nervous system such chronic disease states 5, the partial prevenas central nervous system microbial infec- tion of these disease states in man and anitions, brain trauma due to many causes, and mal models with superoxide dismutase

TIPS -February 1983 administration, and the always greater therapeutic effectiveness of copper complexes in models of these diseases implies an etiologic role for superoxide anion radical or other more reactive species derived from it. This further suggests a need to better understand normal copper metabolism and changes that occur in chronic life-threatening disease states. Further, since zinc and iron-dependent interactions are known to be involved in facilitating these copper-dependent processes they also merit detailed study as well as other essential metalloelement-dependent processes which may also be involved in overcoming diseasetL These seemingly varied effects of copper complexes can be unified with the recognition that copper-dependent enzymes have roles in the prevention of tissue damage, promotion of tissue repair processes, and modulation of pro-inflammatory responses5. Tissue damage may be prevented as a result of SOD-like activity or the induction of SOD activity and decreasing lysosomal membrane permeability. Tissue repair processes are promoted as a result of lysyl oxidase-like activity or induction of lysyl oxidase activity. Pro-inflammatory responses, including lymphocyte transformation, stabilization of gamma globulin, prostaglandin Ea and F2, synthesis and histaminic activity, have been shown to be modulated by copper complexes. The anti-microbial activity of copper complexes also needs to be restated as a plausible mechanism accounting for the antiinflammatory effects of copper complexes in preventing the inflammatory response due to bacterial, viral and mycoplasmal infections. In addition, a variety of enzymatic activities may be modulated by copper complexes5. It has been suggested that as a result of their SOD-like activity they modulate the microsomal carboxylating system required for the conversion of preprothrombin to prothrombin and account for a possible antithrombotic effect of copper complexes with SOD-like activity. Copper complexes may also modulate glutathione-S-transferase activity by modulating the conversion of the free thiol form to the bound disulfide form and account for a reduction in ghitathione-S-transferase activity in chronic adjuvant arthritis. Observed modulations of iron-dependent enzymes which make and use superoxide anion in catalysing paptide-prolyl and peptide-lysyl hydroxylations, cytrochrome P-450 hydroxylations, NADP-dependent cytochrome P-450 reduction and catechol dioxygenations have also been related to the SOD-like activity of copper complexes.

73 Reading

Dtseases and Copper, Humana Press, Clnfion,

1 Hart, E. B., Steenbock, H , Waddell, J. and Elvehjem, C. A (1928) J. Btol Chem. 77, 797-812 2 Sonenson, J. R. J. (1978)lnorg. Perspect Biol. Med. 2, 1-26 3 Sorenson, J. R J and Hangarter, W (1977) lnflammaUon 2, 217-238 4 Sorenson, J R J (1974) xn Trace Substances m Enmronmental Health (D. D Hemphdl, ed ), Vol. 8, pp 305--311, Umverstty of Mtssoun Press, Columbm 5 Sorenson, J R. J. (1982) tn Metal Ions m Biological Systems (Sngel, H , ed.), Vol 14, pp 77-124, Marcel Dekker, New York 6 Powanda, M C (1981) ha Agents and Acnons Supplement 8 (Rainsford, K D , Brune, K and Wlutehouse, M W., eds ), pp. 121-135, B Lrkhauser, Basel 7 Sorenson, J. R. J. (1979) nn Copper m the Environment, Part 2, Health Effects (Nnagu, J O , ed.), pp. 83--162, Wfley-lnterscnence, New York 8 Leuthanser, S. W. C., Obedey, L W , Obedey, T D. and Sorenson, J R J (1981) J Nat Cancerlnst 66, 1077-1081 9 0 b e d e y , L W and Buettner, G. R. (1979) Cancer Res. 39, 1141-1149 10 Lengfelder, E., Fuchs, C , Yotmes, M and Weser, U. (1979)Biochem. Btophys Acta 567, 492-502 11 Sorenson, J. R J. ( e d ) (1982) Inflammatory

New Jersey

Dr Sorenson earned hts B.Sc. degree m Pharmacy.Chemistry (cure laude) and hts Ph.D. m Medtcinal Chemtstry-B~ochemtstry from the Umversuy o f Kansas, workmg wuh E E Smtssman. From 1965 to 1970 he was a Semor Research Chemist at Searle Laboratortes From 1970 to 1977 he was Asststant Professor at the Universtty o f Cincinnati. He ts now Professor at the Umversuy o f Arkansas and is a member o f the College o f Pharmacy, Department o f Btopharmaceutwal Sctences, and College o f Medtcme, Department o f Pharmacology. Professor Sorenson ts also Director o f the ESsenual Metal Analysts Laboratory

Pain suppressive systems of the brain J. W. Lewis and J. C. Liebeskind Department o f Psychology, Umversay of Cahfornta, Los Angeles, 405 Hilgard A venue, Los Angeles, CA 90024, U.S.A.

Studies o f stimidation-produced analgesia generated the hypothesis that the brain has potent intrinsic mechanisms o f pain suppression, an idea greatly reinforced by the subsequent discovery o f endogenous opioid peptides. At least two analgesia substrates are now thought to exist within the central nervous system. Opioid peptides appear to play a significant role in only one o f these. A focus o f recent interest has been in determining the natural stimuli that activate endogenous mechanisms o f analgesia. Certain forms o f stress seem to have this property. Intractable pain is a major health problem in the world today. Although the neural and neurochemical substrates of chronic, pathological pain and of normal pain perception are certainly not the same, some key discoveries made in the last decade elucidating basic properties of nociceptive systems seem to be influencing what we think and do about chronic pain disease. This review will focus on one set of such discoveries, those suggesting the existence of powerful pain-suppressive mechanisms intrinsic to the central nervous system. The vast majority of this work has been conducted on laboratory animals, but human applications have already been made and the early results appear promising. We have recently written a somewhat

longer review 14 to which the interested reader is referred for a more complete bibiiography than can be included here. Stimulation-produced analgesia (SPA) In 1969, Reynolds fwst showed that electrical stimulation of a portion of the medial brain stem, the periaqueductal gray matter (PAG), produced analgesia in the rat so profound as to permit abdominal surgery without anesthesia~L Our laboratory, and now many others, have confirmed and greatly extended this original observation. PAG stimulation causes analgesia matched only by moderate to high doses of morphine in a variety of standard analgesiometric tests ~¢t5. This analgesia appears to represent a true pain suppression and not be sew,-

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