SIGMA RECEPTORS

Sigama receptors are perhaps one of the most complex and confusing topics in the receptor pharmacology. They were previously classified as opiate receptors. According to some researchers they are not receptors at all but just enzyme binding sites. According to others they may be steroid receptors or intracellular messenger binding sites since they are present on microsomes and not on cell surface. They also recognize several important classes of psychotropic drugs: 1. antipsychotics like haloperidol 2. psychomimetics like phencyclidine (PCP) 3. some synthetic opiates like pentazocine 4. some psychostimulants like cocaine Considered as type of opioid receptors because: 1. Many morphine derivatives bind to them 2. d-stereoisomers of benzomorphans (pentazocine and cyclazocine) were found to have no effect on mu, kappa and lambda receptors but still reduced coughing. So it was thought that some opiate like (opioid) receptor was missing. Arguments against this are: 1. Endogenous opioids (endorphins, enkephalins) have little sigma activity. 2. These receptors are activated by non-opioids too. 3. Their functions are mostly unrelated to those of opiate receptors. 4. Isolated and cloned receptors have no structural similarity to opioid receptors. SIGMA RECEPTOR SUBTYPES By studying the binding properties of PCP analogs it was suggested that sigma receptors may have multiple subtypes. SIGMA 1 RECEPTORS 25 kda polypeptide has been cloned Also coupled to other receptors, notably nicotinic cholinergic and NMDA glutamate receptors. Have no structural similarity to opioid receptors. Endogenous ligands: <when we talk of a receptor there must be a natural ligand in the body to bind them> Here no natural endogenous ligand has yet been found. 1. Endogenous ligands have little affinity for it 2. Substance P was previously considered to be one. 3. A ligand has been proposed and called angeldustin or endopsychosin (but yet not found) 4. Dehydro-epi-androsterone may be an agonist 5. Progesterone may be an antagonist. Among pharmacological agonist are: Ibogane, Pentazocine, DTG (1,3 di-o-tolyguanidin), PCP, cocaine, opates, dextromethorphan

Antagonists include: some antidepressants, metaphit Modulation: chronic amphetamine use upregulates these receptors. long-term antidepressants and antipsychotic therapy down-regulates them. Methamphetamine increases sigma receptor binding affinity. Location: cerebellar cortex, cerebral cortex, nucleus accumens, limbic areas, extra-pyramidal motor system, pineal gland, liver, kidney, endocrine glands, intra-cardiac parasympathetic neurons, placenta, immune system, most tumour cells. Sigma 1 activity: 1. Hallucinations 2. Dysphoria (dysquiet, restlessness, malaise) 3. Cardiac stimulation 4. Prevent rejection of graft by inhibiting T-cell immunity 5. Counteract some of analgesic action of opioids 6. Psychotomimetic or psychosis-like effects from schizophrenia and drugs (chronic activation by an endogenous abnormal protein is probably the cause of schizophrenia) ( They are involved in amphetamine psychosis from heavy dose of psychostimulants) 7. Inhibit tumour growth 8. Noradrenaline stimulated synthesis of melatonin in pineal gland 9. Affect memory function , reversing the impairment in memory caused by drugs such as pchloroamphetamine and ketamine derivatives (e.g. MK-801) 10. Oligodendrocyte differentiation 11. Cardiac stimulation (Sigma-1

receptors are directly coupled to K+ channels in intracardiac neurons. Furthermore, their activation depresses the excitability of intracardiac neurons and is thus likely to block parasympathetic input to the heart.)
12. Pupillary dilatation 1. May increase nicotinic activity 2. May be involved in emotions (limbic area) 3. Probably involved in prevention of seizures 4. May be involved in development, cellular regulation or other biological processes (suggested by their wide distribution) 5. Anti-amnesic effects in the hippocampus of animals 6. Near Death Experiences (with NMDA glutamate receptors) 7. Migh participate in NGF induced neurite sprouting --> certain antidepressants may facilitate this SIGMA 2 RECEPTORS Sigma 2 receptor is a 21 kda polypeptide very similar to sigma 1 receptor. It seems linked to potassium channels and its neurotransmitter may be Zinc ion. Sigma 2 receptor activation potentiates NMDA receptor funtions. Chronic activation inhibits proliferation and induces apoptosis in a wide variety of cells. Agonist: Ibogaine being tested as a cure for heroine addiction. SIGMA 3 RECEPTORS A recent discovery,sigma 3 receptors are linked to tyrosine hydroxylase and may increase rate of dopamine synthesis. So they may be responsible for stimulant effects of Dextromethorphan. They are targetted by tetrahydronaphthalene derivatives.