Introduction

A systemic administration of CNS drugs is not well controlled. In addition it entails a substantial number of undesired effects, since it includes a distribution of the agent in the whole body. The blood-brain barrier and the liquor-brain barrier are for many drugs (e.g. peptides) an almost impermeable obstacle. Consequently only small amounts of a systemically applied dose can reach its intended CNS receptor target and the time to an onset of effect is significantly delayed. For example anti-depressant tablets must be taken for weeks before they begin to induce substantial improvements in a depressed person's mood.

Generally in a systemic intervention drug effects and their extent of clinical efficacy are determined by pharmacokinetic parameters. Systemic effects correlate with the drug's time/concentration curve resulting from absorption, distribution, metabolism and elimination. A provision of a topical thus a direct agent-receptor reaction can exclude preceding pharmacokinetic processes. Such kind of a direct reaction represents a topical chemosensory receptor intervention on the level of olfactory chemoreceptors. In essence this mechanism is based on a local „revolving door" effect of the agent at a sensory input-receptor followed by an effect execution via endogenous mediators (neurotransmitters, neuromodifiers, hormones). A therapy which creates therapeutic CNS effects by this kind of pharmacodynamics can be considered as a topical chemosensory medicine.


The neurophysiological basis of chemosensory signaling

The primary CNS processing center for emotions is the limbic system. Part of this brain structure is the hypothalamus which functions as a "biological interface" for the control and coordination of the emotional circuitry, including the autonomic nervous system and pituitary gland. Since embedded in deep layers of the ventral part of the diencephalon this target can not be sufficiently activated by means of conventional pharmacological dosing without producing systemic side effects.

Topography of the Limbic Brain

On the other hand a number of its neuronal projections can be more easily activated. A respective input structure is the olfactory region (OR), the sense of smell. In humans the olfactory region is located in the upper part of the third nasal conchae. Its epithelium contains chemoreceptors - sensory receptors selective for chemicals - which convert incoming chemical information into neuronal signaling (i.a. e.g. Christensen, TA, Heinbockel T, Hildebrand JG, J. Neurobiol 30(1) 82-91(1996). The OR chemoreceptor cells are neuronally connected with a front part of the brain, the olfactory bulb (OB), which projects to the piriform cortex (primary olfactory cortex), hypothalamic nuclei (e.g. paraventricular nucleus; PVN, supraoptic nucleus;SON) and some other cortex structures (for further in depth information see: pp 159-203 & 377-416 in „The synaptic organization of the brain", Gordon M. Shepherd, (Editor) 4th Edition, Oxford University Press, New York,1998). An initial cluster of neurons in the olfactory bulb, the glomeruli, receive their direct input from the olfactory chemoreceptor neurons and have synaptic connections with a second cluster of neurons, the mitral cells. The mitral cells build, together with other interneurons (such as e.g. the tufted cells) a complex processing circuitry in the olfactory bulb. The analysis of this circuitry reveals that it technically includes convergence processes (signal amplification), lateral inhibition (signal profiling) and recurrent inhibition (adaptation). (i.a. e.g. Mori, K, Nagao H & Yoshihara Y, Science 228 (5540) 711-4 (1999). This kind of input processing means that occupation of just a few OR chemoreceptors can effect significant CNS signals. In order to execute externally induced effects the OB circuits interact with hypothalamic nuclei which trigger other neuronal circuits and hormone systems.

Simplified model of the chemosensory input circuitry OR: Olfactory Region, OB: Olfactory Bulb, HT: Hypothalamus HT1-3: intra-hypothalamic nuclei

Molecular mechanism of chemosensory signal transmission

The transnasally inhaled molecules are bound to the OR chemoreceptors. Functional groups of the molecules interact with specific sub-sites within the OR receptors to generate the receptor response - the transduction - a second messenger cascade. The receptors activate G-protein mediated a cyclic nucleotide-gated non specific ion channel. This generates a brief fluctuation in the membrane potential, caused by a rapid opening and closing of the ion channels, a depolarizing current. The resulting action potentials transmit the chemically induced signals to the OB where a process of "signal pattern profiling" takes place (i.a. e.g. Pilpel Y, Sosinsky A & Lancet D; Essays Biochem. 33:93-104 (1999).

A spatial signal pattern is distributed to the hypothalamic interface and to various cortical structures (i.a. e.g. Amygdala) and effects secondary biochemical reactions (neurotransmitter, hormonal) in both central and peripheral targets.

Synopsis of chemosensory signal transmission

The biochemical cascade in this chemosensory mechanism is a direct analogue to the optical transduction of the visual apparatus. The only difference is that its effects are triggered by chemical agents instead of different levels in free physical energy as it is the case there.


Specific aspects of chemosensory pharmacology

The pharmacological mechanism of a chemosensory effect is basically different to a systemic administration. All effects base on two steps only: A local „revolving-door effect" of the agent ("inducer") at the input-chemoreceptor and a biophysical effect execution via endogenous mediators (neurotransmitters, neuromodulators). The inducing agent does not permeate into the body. Its action is limited to a temporary contact with the receptor ("receptor imprint") in order to trigger the receptor reaction, the transduction.

„Revolving-door effect" at the input-chemoreceptor (R: topical chemoreceptor, gray: inactive (stand-by), red: activated (signaling)

Right after binding and "receptor imprint" the inducing molecule undergoes its terminal elimination at the input receptor level and is exhaled ("revolving-door effect"). Its excretion can take place either in form of a locally inactivated break-down product or as unchanged molecule. The simultaneous cascade of afferent signaling which is induced after "receptor imprint" is entirely dissociated from the physical presence of the inducing chemical molecule. The CNS bioresponse is triggered by the chemically induced "isomorph" neuronal information pattern and may include secondary or tertiary central and/or peripheral reactions of endogenous mediators (neurotransmitters, neuromodulators, hormones). The input chemoreceptor switches from an activated (signaling) to an inactivated (non-signaling) stand-by status ("Flip-Flop mechanism") and is ready for a subsequent action.


Differences of a chemosensory process to a systemic application

A general descriptive characteristics for the chemosensory processes is their rapid onset of CNS effects. The cause is that the agent-receptor reaction takes place right at the input receptor level and that it is based on a fast biophysical process. The whole signaling process takes place in neuronal structures and is executed by neurotransmitters and neuromodulators. In contrast to this a systemically administered agent (e.g. such as a "nasal" application) has to physically pass different levels of pharmacokinetic processes such as

Difference routes for a topical chemosensory effect and a systemic "nasal" application

absorption, distribution metabolism and elimination before it can approach its CNS target receptor. All these pharmacokinetic processes (diffusion) are slow and since they require the physical presence of the agent in the body they also include a significant safety disadvantage compared to the topical chemosensory intervention.

Rapid onset of CNS effect in a chemosensory intervention compared to a systemic administration

A principal descriptive differentiation between a topical chemosensory effect and a systemic drug effect can be made by employing a mathematical relation that includes a relevant pharmacokinetic constant for the agent. Such a relation is

This relation is typical for topical chemosensory effects only and can principally not be met by any systemic route of application, such as e.g. a conventional "nasal" application.


Pharmaceutical conversion of a chemosensory process

The induction of an externally controlled brain signaling requires the application of aerial (gaseous) trails that sufficiently transport the biological or chemical agents to the chemoreceptors. Suitable formulations need for this purpose a gas phase with a colloid

Example of an implemented CDS (Chemosensory Delivery System)

dispersion. Such trails can be released by specific devices for a topical sensory inhalation. Conventional "sprays" do not sufficiently fulfill such requirement. Therefore specific delivery systems have been designed for this purpose. Drug delivery systems are defined as technical devices which provide a controlled release of agents. Chemosenory Delivery Systems (CDS) represent a specific technique of drug delivery systems for a controlled emission of chemosensory vectors (volatile chemical trails). There are currently two major directions in their practical technical application. This are either active or passive patch like CDS or spray devices which produce gaseous (molecular) sprays with implemented CDS.


Chemosensory Medicine

A chemosensory medicine can be defined as:

We have evidence for the induction of topical chemosensory effects for various natural substances. One of them is the biological neuropeptide Oxytocin, which rapidly induced on this specific route anxiolytic and anti-depressive effects. Principally suitable candidates for a chemosensory medicine are all those natural agents which have, due to evolutionary aspects, a high affinity to olfactory chemosensory receptors. This are e.g. various hormones, pheromones, smaller peptides and some essential oils and/or some of their ingredients. Also some agents which are used in the so-called "aroma-therapy" appear to trigger chemosensory effects. In addition a couple of chemical-synthetic agents may induce topical chemosensory effects which base on a functional (allosteric) receptor reactions i.e. a binding with receptors of 2nd order. It is also likely, that in some cases where rapid CNS effects have been described for a "nasal" route these are primarily due to a chemosensory effects and not a systemic action, in particular with such agents which are known to react with G-protein receptors. A further respective clarification can be reached by application of the T eff << C max relation.

Therapeutic areas which can be principally considered for an application of a chemosensory medicine are:

Summary

A topical chemosensory receptor intervention on the level of olfactory chemoreceptors is based on a local receptor effect by a centrally acting chemical molecule (the "inducer") and which triggers a biophysical signaling. The action of the inducer is limited to a temporary contact ("receptor imprint") and the molecule is hereafter eliminated („revolving door effect"). The CNS bioresponse is triggered by afferent neuronal signal patterns which effects secondary reactions of endogenous substances and is dissociated from the physical presence of the inducer. The pharmacological mechanism is principally different to a systemic administration since it excludes pharmacokinetic components. A differentiation between a topical chemosensory effect and a systemic drug effect can be made with the descriptive relation Teff << Cmax. A chemosensory medicine represents the therapeutic use of the topical chemosensory receptor intervention. It employs chemosensory delivery systems (CDS) and provides for various therapeutic CNS indications the possibility of more selective, faster and safer effects than a systemic drug administration.