K-Agonist

Opioids Buprenorphine, K agonists Buprenorphine probably not effective in treating stimulant abuse. K Agonists have not been adequately smdied. 

Like <5 selective agonists, k agonists have few of the side effects of morphine and recent studies have suggested that k selective agonists may be effective analgesics [2]. However, a limitation to the clinical use of k agonists is tolerance development. 

Overall, p agonists increase transmission in the mesolimbic dopamine system (Devine et al. 1993 Johnson and North 1992). They inhibit GABAergic neurons in the ventral tegmental area, disinhibiting dopamine activity. In contrast, k agonists inhibit dopamine release in the same system. As with other drugs of abuse, an influence on the mesolimbic dopamine is believed to mediate the positive reinforcing effects of opioids. 

Interactions are seen between cocaine and the opioid system in analgesia. A synergistic effect occurs when cocaine is combined with a ju agonist (morphine) in the hot-plate test and a k agonist (U69,593) in the hot-plate test (Waddell and Holtzman 1999). Cocaine enhances morphine analgesia in several analgesic paradigms (e.g., formalin test, hot-plate test, and thermal tail-flick test)... 

All pure p agonist opioids produce a dose-related depression of ventilation. Pure K agonists have little effect on respiration. The primary effect of opioids is a reduction in the sensitivity of the respiratory centre to C02. They also depress the medullary and peripheral chemoreceptors. Initially, respiratory rate is affected more than tidal volume, which may even increase. With increasing doses respiratory rhythmicity is disturbed resulting in the irregular, gasping breathing characteristic of opioid overdose. The hypoxic drive to ventilation is also depressed by opioids. 

Effects of autonomic blockade on the response to phenylephrine (Phe) in a human subject. Left The cardiovascular effect of the selective K-agonist phenylephrine when given as an intravenous bolus to a subject with intact autonomic baroreflex function. Note that the increase in blood pressure (BP) is associated with a baroreflex-mediated compensatory decrease in heart rate (HR). Right The response in the same subject after autonomic reflexes were abolished by the ganglionic blocker trimethaphan. Note that resting blood pressure is decreased and heart rate is increased by trimethaphan because of sympathetic and parasympathetic withdrawal. In the absence of baroreflex buffering, approximately a tenfold lower dose of phenylephrine is required to produce a similar increase in blood pressure. Note also the lack of compensatory decrease in heart rate. 

Clinical failure of K-agonists because of psychotomimetic side-effects... 

In compounds with stronger p-agonistic activity (buprenorphine and pentazocine), the abuse potential is marked and in contrast to earlier estimations, both compounds had to be subjected to narcotic control. In compounds with a marked K-agonistic component (cyclazocine, nalorphine) the dysphoric side effects are so prominent that the compounds could not be used for therapeutic purposes. 

Expression of peripheral opioid receptors and peptides seems to be triggered by immunological and inflammatory processes, and it is speculated that these opioid receptors represent a second peripheral pain inhibitory system. This has triggered an intensive search for peripherally-acting k-agonists, which are devoid of the centrally-mediated psychogenic side-effects and which are believed to be attractive new compounds for the treatment of traumatic, inflammatory and burn-induced pain. 

Respiratory depression is most prominent with p-type opioid compounds and less so with K-agonists and 5-agonists. 5-Agonists seem to have a compensatory stimulant action component, which counteracts respiratory depression. 

Table 3.6. ANTAGONIST K/VALUES (NM) FOR 3-HYDROXYCYPRODIME (34) IN THE MVD AND GPI AGAINST k AGONISTS [77]...

Ergocornine] Claviceps purpurea, C. spp. (ergot JJ2-K agonist [ergotism... 

MethysergideJ Semi-synthetic 5HT1-K agonist 3H12-R... 

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