I just want to address one part of this at this time. This will be lengthy... my apologies.
(10-29-2009 8:05 AM)Gone with the Wind Wrote: [...]Another is that most drugs have chemical effects through getting in the bloodstream, either through the skin, inhalation, ingestion, or injection. Pheromones seem to work by triggering sensory neurons of some kind and sending specialized information to the brain for processing. Humans respond differently than pigs or insects, I believe, because of the involvment of cortical processing functions in addition to the lower functions found in insects and swine.
We don't know that what you have stated above is fact. And even if it is the case that these only bind/stimulate receptors, that does not rule out the possibility for negative consequences.
Understand that the neuronal surface cell receptors in the olfactory canal are part of the nervous system. They are expressed on the surface of the olfactory mucosal surface (and on the epithelial surface of the lungs), and are therefore not protected by the blood/brain barrier, but rather are exposed and vulnerable to the outer environment. Yet their neuronal bodies are in communication with and affect neurons that are protected by the blood/brain barrier.
The definition of a receptor is a molecular structure in a cell or on the surface of a cell that allows binding of a specific substance that causes a specific physiologic response. In the case of nerve cell surface receptors, the specific physiologic response will be either inhibitory on the nerve or excitatory on the nerve, inhibiting or enabling the release of specific neurotransmitters from that nerve cell, which in turn changes the "state" of nerve cells with which it is in communication (which are many).
AMPA receptor is one such neuronal receptor found in the olfactory passage - This is an ionotropic receptor. It binds ozone and other ionic substances. In people with allergic disease the binding of ozone results in an increased activity of sensory nerves in the upper airways with a subsequent increased release of neuropeptides. In addition to the known ozone-induced release of proinflammatory mediators, these mechanisms may explain the increased responsiveness of patients with hypersensitive airways.
AMPAr binds 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine which is an anticonvulsant drug. It binds certain axiolytic drugs which act as modulators on this receptor. It binds certain diuretic and antihypertensive drugs. Certain modulating compounds which bind to this receptor have memory and cognitive effects (both positive and negative).
AMPAr also binds Glutamate, which is the main excitatory neurotransmitter released by nerve cells. AMPAr also is inhibitory on Glutamate release under certain conditions. In the nose AMPAr binds ionic substances like ozone, volatile fatty acid butyrate and propionate, and free protons (H+).
NMDA receptor is another neuronal receptor expressed in the olfactory passage. It is also an ionotropic glutamate receptor. The loss of NMDA receptors through aging is implicated in the characteristic chronic anxiety and restlessness seen in Alzheimer's disease. In the nose NMDAr binds the antagonist (inhibitory) hallucinogens and anesthetics and dissociative recreational drugs, causing the inhibition of glutamate release.
Over activation of either of these receptors with glutamate or a glutamate analog (such as aspartate) on these receptors causes excitotoxicity which in turn causes all the post synaptic nerve cells to be damaged or destroyed. Any substance that strongly increases the release of glutamate in neuronal tissue can have this affect if it binds to either of these two receptors.
nACh (Nicotinic acetylcholine) receptors express on the surface of the bronchial epithelium. These are activated by nicotine, where it is mainly excitatory on these neurons.
G-Protein Coupled Receptors (GPCRs) are the main receptors involved in odor detection. They are "slow" activators of neurological response either through cAMP or phosphatidylinositol pathways. They have binding affinity to pheromones, hormones, and neurosteroids. Most classes of these surface receptors mainly bind axiolytic and anti-halucinogenic substances which down-regulate NMDAr and AMPAr excitability, but certain subtypes of this class of receptor are excitatory on NMDAr and AMPAr. GPCRs also bind serotonin, GABA, Bombasin, Dopamine, epinephrine, norepinephrin, oxytocin, and Glutamate. (Serotoin and bombesin are components of vaginal fluid from secretions via the Bartholin's gland.) These receptors are involved in immune and allergic response as well. Blood pressure, heart rate, and digestive processes are controlled through nervous system transmission via GPCR pathway regulation of both the sympathetic and parasympatheic nervous systems. GPCRs down regulate when they are overexposed to their activating substances and that produces desensitization to the activating substances.
GPR30 is a G-Protein Coupled receptor that is expressed in the nasal passage. This receptor binds 17b-Estradiol in the presence of a fixed concentration of progesterone, which causes a 3-4 fold increase in the release of LH. LH increases progesterone and testosterone production. R-carvone, a component of spearmint essential oil, when binding to this receptor increases LH release by 1000 fold.
GABAA receptors are found in the olfactory nasal mucosa. GABA is the main inhibitory neurotransmitter in the central nervous system. In addition to binding GABA, GABAA receptors also bind benzodiazepines, nonbezodiazapines, barbiturates, ethanol, inhaled anaesthetics, and neuroactive steroids. Binding of these substances to GABAA receptor produces either anti-anxiety effect or sedation.
Androstandiol (5a-androstan-3α-ol-17b-ol) also binds and positively modulates GABAA receptors (Frye et al., 1996) with potent anxiolytic (anti-anxiety) and anticonvulsant activity (Frye and Reed, 1998; Reddy, 2004ab), and Androsterone has similar activity (Kaminski et al., 2005)..
Allopregnanolone (5a-pregnan-3a-ol-20-one) and allotetrahydrodeoxycorticosterone (5a-pregnane-3a,21-diol-20-one) are also positive modulators of GABAAr (Puia et al., 1990) and have anticonvulsant (Rogawski and Reddy, 2004) and anxiolytic (Rodgers and Johnson, 1998; Bitran et al., 1991; Finn et al., 2003) activity. Alpha Androstenol is a positive modulator of GABAA receptors comparable to the ones mentioned above (Rafal M. Kaminski, Herbert Marini, et al 2006).
Pregnenolone sulfate and DHEA sulfate also bind to GABAA where they act to block and inhibit the action of this receptor. Blocking and inhibiting this receptor may cause anxiety and restlessness.
There are many, many other surface receptors, some involved in cell repair, some involved in immunologic response, some involved in sensory modulation. The point is each of these, when activated, start chain reactions that grossly affect the whole person.
And we've just begun to classify all the receptors found on the mucosal surface of the nasal cavity and the lung. Over 400 have been identified in the nose. Most of these identified receptors are still considered orphans, meaning the binding substances have yet to be found and of course their activity is unknown.
Diane