Are there too many neurotransmitters?

Are there too many neurotransmitters?

Are there too many neurotransmilrters’l DcpPrrment of Ffturmacoli?~, College of kdicine, Chlicago, Illinois 60680, U.S.A. *-- The single most influen...

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Are there too many neurotransmilrters’l DcpPrrment of Ffturmacoli?~, College of kdicine, Chlicago, Illinois 60680, U.S.A. *--

The single most influential concept guidjng the development of neurophar.nacology has been that of newochem&zl The vast majority of transmission. explanations of sites and rn~h~isms of drug effects on the centrai nervous system are based on this concept. In addition, many new agents have originated through a designed attack on specific ~rn~n~~ of the neurotransmission process. As a result, pharmacologists have generally welcomed each new putative neurotransmiser as signaling more neurochemical pathways and receptor systems available for pharmacological manipulation. Present concepts of neurotransmission seemingly re$r:sre only a binary coded (excitor sr idiots) message possibly [email protected] xi with a duration factor. Since even The recoding of the excitatory or inhibitory d rection of the message is frequently carrted by the postsynaptic rzeptor, rather tharz ihe transmitter. there seems to be a limited need for different types of transmitter agents. However,, as a result of rapid developments in r~io~~~y and im munohistochemical techniques. the relatively circumscribed population. of potential neurotransmitters has suddenly exploded. The rapidity of the expansion in the number of neurosecretory sub%3nces, at present, seems limited only by rhe rate at ,which new spxific antibodies can be raised. Alr&y, the number of classes of nenrosecfetory agents (e.g. ztino acid&, biogcnic tines, purines, rlolypeptides), let alone thci number of individual c&nts, strain the doctrine of pa4marrj‘ nhzij applied to the concept of imm&cmi~cal transmission. Still, with continuing regularity, most papers which describe a nl~vvchemical enthy specifically IoeaBzed within neurons, and/or released following nerve stimulation, proceed to suggest that that agent could function as a

concentrations of the more widely accepted neurotransmitters OABA, serotonin (bHT), and no~inephrine (NE). The amino acid GABA is localized in interneurons while the monoamines occur in neurons originating from cell bodies situated in the brain stem. Other neuropeptides present in the apinal cord, l.fniwet~it_vof Illinois at rke Medical Center. though not selectively localized to the substantia gelatinosa include TRH, and neurotensin. In reflecting on the extraordinary neurotr~smitter. The resulting superpotpourri of neuropeptides localized in abundance of putative neurotransmitters is beginning to embarrass the lack of need the spinal cord, a number of questions give pause in accepting the temptation to for so many agents in our current concents of n~rotr~~i~ion. Thus, the simply regard them as new neurotransmitter candidates. Why should neurons rapidly proliferating number of neurotransmitter candidates now demands use such structurally complex and metabolically expensive substances as a some serious rethinking of the possible tridecapeptide to carry a simple inhib;~o~ roles neuro~reto~ agents play in inforor excitatory message? Further, why do mation transfer. No group of putative neurotransmitters primary afferents need four different gives greater impetus to these questions neurotransmitters (i.e. substance P, somatostatin, VIP and CCK)? If, as some than the polypeptides. The surprisingly discrete patterns of distribution within the have postulated, substance P serves as an and somatostatin as an CNS of many familiar peptides have excitatory inhibitory neurotransmitter why do we already caught us with an inappropriately need more peptides in affercnt terminals? narrow nomenclature. Thus such designaEven more disconcerting is the growing tions as th~otropin releasing ho~one evidence that more than one neurosomatostatin, vasoactive (TRH). intestinal peptide (VIP) and cholecystosecretory substance can be localized in the same neuron. There is evidence that both kinin (CCK) seem quite out of place when 5-HT and substance P can be located in applied to peptides locali& in primary the same bulbospinal neurons, and that afferent terminals or intermurons within the spin&! cord. Furthermore. the iarge NE and somatostatin sometimes appear in the same neurons. Why do some neurons number cf polypeptides localized within require two neurosecretory agents? What minute anatomical areas strains available anatomic~ te~~olo~ in attempts to additional messages do they carry? One caveat, which is repeatedly introdescribe their localization. Nowhere is thii better illustrated than in the narrow c‘luced in an attempt to deal with the band OFtissqre which caps the dorsal horn surfeit of neurosecretory agents, is to of the spinal cord known as the substantia l&el them as neurom~ulato~. The lack geiatinosa. This area, which includes the of precise definition for this term renders Fecond and third laminae of the spinal its usage hazardous. However, if one cord gray matter, is no more than 150-200 accepts as a working definition that m wide in the rat. Yet, it contains an ml~rorn~u~t0rs are neurosecretory extraordinary number of neurosecretory agents which have little effect of their own substances which are sequestered in on postsynaptic membrane but significantly alter the efficacy of other transprimary afferent terminals, descending axons or the relay neuroas present in this mitters, we have done little to resolve the area. Pol~tid~ s&ctiveIy local&l in pyobkm of too many substances. Fc, the substaptia gelatinosa include subexample. it would appear that 5-HT fu:’ fiis this definition of a ncuromodulator stance P. somatostatio, CCK, VIP, angiotemin II and enkcphalin. Of these when it has little effect of its own on peptides, the first four are loca&ed in msoton~o~, but profoun~y increases primary affcrent terminals. The subt!heir response ta glutamate and synaptic stantia gelatinosa also contains high stimulation. If 5-HT is a neuromodulator,


some serotonergic neurons projecting t;, motoneurons need a second neuromodul,ltor in the form of substance P? Thus. at present, the introduction of the term neurom~ulator offers us little resolution to the problem of too many n~~rosecretory sub~ances. At this point it is worth recalling that the behavioral literature is replete with reports that ~~y~tid~ can alter complex behaviors involving memory, pain, drug tolerance and endocrine responses. Projecting from these kinds of findings, perhaps it is time to ask if we are missing im~rtant data regarding peptidergic effects because we are focused too their action finely when studying p~marily at the single unit lectel. The stri;c:oral complexity of the polypeptides, as compared to the amino acids or biogenic amines, should allow these molecules to carry more complex messages which can establish patterns of response rather than simple directionality, Such integrative functions seem to offer a more reasonable basis for the existence of such a large variety of peptides within a modest structure like the subsrantia gelatinosa. For those investigators interested in unraveling the functions roles of the neuropeptides, it seems reasonable to suggest the spinal cord as an organ preparation offering great potential for yielding valuable answers. The unique advantages of spiaal cord preparations are: the fairly clean separation of afferent and efferent pathways into dorsal and why


ventral roots (with the exception of fine diameter afferents in the ventral roots}, the possibility for modality specific stimulation. simple isolation from higher centers by transection, and relatively welldefined anatomical organization with assigned physiological functions. In addition, satisfactory amphibian and rat neonatal spinal cord preparations can be studied in vitro by su~rFusion of the hemisected cord or arterial perfusion of whole cord under conditions which allow control of the ionic environment. Also, tissue culture of cord explants or clonal cell isolates can be maintained. This variety of preparations allows definitive neurophysiological and/or biochemicaf ex~~ments to be executed to answer important functional questions. The functional complexity of the spinal cord also allows the study of synaptic events ranging from simple monosynaptic responses co compIex multisynaptic reflexes which exhibit such long duration effects such as post-tetanic ~tentiation, long-latency presynaptic inhibition, and habituation. Unfortunately, the most interesting structure to study with respect to its surfeit of neuropeptides and biogenic amines, the substantia gelatinosa, is composed of unusually smah cell bodies (6-12 Mm) which makes single unit studies very difficuh. However, it can be studied on an input-output basis Hith respect to its regulation of primary afferent depolarization. This phenomenon atone has sufficient complexity to offer multiple opp )rtunities for studying

Hepaticclearancesof drugs and metabolites K. Sandy Pang Mafhemarid models 0s aperutionalunits hove rheirusefulness, but rheirmeuningsore not absolute. A god exOnrpeis provided in rhe use of simplijied muthematicaimod& in the ~p~e~tut~o~ of the intricatec~rn~iexiti~of the liver. Drug elimination from the body proceeds primarily by renal excretion and biotrans-

formation, Some drugs. especially those lipophilic in character, are readily reabsorbed by the peritubuhrr cells of the

kidney. Unless the drug is biotransformed more polar metabolites that are ultimately excreted, the drug will remain in the body, mostiy in fatty tissues, for long periods of time. The manner in to

integrative multisynaptic reflexes and activity patterns. The complexity of this system can be simplified. to some degree, through the use of pharmacological toots. The GABA system can be selectively depleted by treatment with semicarbazide. the 5-HT and NE neurons can be selectively destroyed by the neurotoxins 5.7.dihydroxytryptamine and ~hydroxydopamine, respectively. The enkephalin system can be antagonized by naloxone. and substance P can be depleted with capsaicin. However, lnuch work is needed towards defining the specificity of these tools, and the development of new pharmacological agents which affect the other neuropeptides. In summary, established theories of neur~hemical transmission have fittle need for the rapidly expanding number of neurosecretory agents being identified. A time of serious rethinking of our current concepts is ahead of us, and Neropharmacolog~ts have manv unusual opportunities for making major contributions towards renovating current concepts or perhaps generating some radically new theories. In this process, the unusually rich complexity of the neurochemistry of the spinal cord, together with its relatively well-defined anatomy and physiology provides a unique tissue in which to exploit these opportunities.

which drugs are biotransformed depends on the structure of the drug moiety. Should their structures mimic compounds that are native to the body, biotransformation would most likely be mediated through