animals with increased food intake, decreased energy expenditure, and obesity. They also show insulin resistance and increased blood levels of leptin and insulin. It is not yet known whether the Hi receptor has a similar role in humans ‘The "Triple Response" Intradermal injection of histamine causes a characteristic wheal-and-flare response that was first described over 60 years ago. ‘The effect involves three separate cell types: smooth muscle in the microcirculation, capillary or venular endothelium, and sensory nerve endings. At the site of injection, a reddening appears owing to dilation of small vessels, followed soon by an edematous wheal at the injection site and a red irregular flare surrounding the wheal. The flare is said to be caused by an axon reflex. The sensation of itch may also accompany the appearance of these effects. The wheal is due to local edema. Similar local effects may be produced by injecting histamine liberators (compound 48/80, morphine, etc) intradermally or by applying the appropriate antigens to the skin of a sensitized person. Although most of these local effects can be blocked by prior administration of an Hy receptor-blocking agent, H2 and Hy; receptors may also be involved. Other Effects Possibly Mediated by Histamine Receptors In addition to the local stimulation of peripheral pain nerve endings via Hs and Hy receptors, histamine may play a role in nociception in the central nervous system. Burimamide, an carly candidate for H; blocking action, and improgran, a newer analog with no effect on I), Hs, or Hs receptors, have been shown to have significant analgesic action in rodents when administered into the central nervous system, The analgesia is said to be comparable to that produced by opioids, but tolerance, respiratory depression, and constipation have not been reported. Although the mechanism of this action is not known, these compounds may represent an important new class of analgesics. Other Histamine Agonists Small substitutions on the imidazole ring of histamine significantly modify the selectivity of the ‘compounds for the histamine receptor subtypes. Some of these are listed in Table 16-1. Clinical Pharmacology of Histamine Clinical Uses In pulmonary function laboratories, histamine aerosol (in addition to other agents) is used as a provocative test of bronchial hyperreactivity. Histamine has no other current clinical applications, Toxicity & Contraindications Adverse effects of histamine release, like those following administration of histamine, are dose- related. Flushing, hypotension, tachycardia, headache, wheals, bronchoconstriction, and gastrointestinal upset are noted. These effects are also observed after the ingestion of spoiled fish {scombroid fish poisoning), and there is evidence that histamine produced by bacterial action in the flesh of the fish is the major causative agent Histamine should not be given to asthmatics (except as part of a carefully monitored test of