## 1 Introduction  
In July 1894, Dr. [PERSON] presented the poison isolated from aqueous extract of ovaries of globefish at the monthly meeting of the Pharmaceutical Society of Japan. Later, he established an improved method for extraction and purification suitable for large-scale production of the poison.  
Finally, in 1909, he confirmed that globefish contains only one toxic substance and named it tetrodotoxin (Figure 1) due to the name of the family of pufferfish from which it was first isolated, _Tetraodontidae_[1].  
At first, it was believed that TTX was present exclusively in pufferfish of the family _Tetraodontidae_, and it was controversial whether TTX in the fish was endogenous (produced by the pufferfish itself) or exogenous (taken from the outside and accumulated). In 1964, this toxin was unexpectedly detected in the Californian new _Taricha torosa_[2] breaking the above belief. Since then, TTX has been detected in both marine [3, 4, 5, 6, 7, 8, 9] and terrestrial species [10, 11, 12, 13]. Moreover, the TTX intoxication of the trumpet shell following the ingestion of toxic starfish [7], TTX production by marine bacteria [14], the facts that pufferfish become non-toxic when artificially reared with non-toxic diets [15, 16, 17] and that such non-toxic pufferfish become toxic when fed TTX-containing diets [18, 19, 20], have pointed out that the main mechanism of TTX accumulation in pufferfish is the food chain, consisting of several steps and starting with marine bacteria as a primary source of TTX. In marine pufferfish species, toxicity is generally high in the liver and ovary, whereas in freshwater species, toxicity is higher in the skin.  
Although TTX-bearers are typical of warm waters and it was regarded as a problem confined to Asian countries, recent studies report the possible migration of these toxic species from the Red Sea to the Mediterranean Sea through the Suez Canal [21, 22, 23].  
TTX, one of the most powerful neurotoxins known, it is about 1200 times more toxic to humans than cyanide and it has no known antidote. This toxin binds to the sodium channels of the excitable tissues in the human body (muscles and nerves) and the inhibition of sodium ions through the channels effectively immobilises these tissues [24]. The severity of the symptoms induced by the TTX is dose dependent [25]. The symptoms included tingling of the tongue and lips, headache, vomiting, muscle weakness, ataxia and even death due to respiratory and/or heart failure [26].  
TTX is responsible for 30-50 cases of intoxications occurred every year [26]. In Japan, a regulatory limit of 2 mg equivalent of (eq) TTX/kg was established for TTX, while in Europe, this compound, considered an emerging toxin, is still not regulated. However, according to the current EU legislation, fish belonging to the poisonous family of fish _Tetraodontidae_ or products derived from it must not be placed on the European markets [27, 28].  
Figure 1: Chemical structure of tetrodotoxin (TTX).  
Because TTX blocks voltage-gated sodium channel and causes paralysis, it can also be applied as a potential pain relief and some researchers are trying to make use of the analgesic activity of TTX to treat various types of pains such as severe cancer pain [29; 30; 31], or to help in reducing cue-induced increases in heroin craving and associated anxiety [32].  
In the present paper, the detailed origin and distribution in nature, the toxicity and mechanism of action and the different medical uses of TTX are thoroughly described.