Delta receptors activation

Delta receptor activation also produces analgesia, but it can also cause seizures as well. Delta receptors normally bind to a class of endogenous ligands known as enkephalins, but unlike mu receptors, information about delta receptors is limited. Enkephalins are peptides that are produced by the pituitary gland. Several different enkephalins have been identified. [3-Enkephalin resembles opiates because when it binds to a delta receptor, it relieves pain.11... 

Delta receptor knockout mice were exposed to alcohol, and drinking was examined in the two-bottle choice and operant self-administration paradigms [73,80]. First, naive animals consumed alcohol as wild-type animals in the two-bottle choice. After training to self-administer alcohol, the mutant mice developed a stronger preference for alcohol and consumed more than wild-type mice in both tests. After alcohol experience also, their anxiety decreased and reversed to wild-type levels. This suggests that, in the case of alcohol, delta receptor activity may partly influence addictive behavior indirectly, by modulating anxiety-like responses. Whether this applies to selfconsumption of other drugs of abuse remains to be determined. 

Enkephalins could be implicated in dopamine mesoaccumbens-depen-dent appetitive motivation and behavioral positive reinforcement by separated mechanisms involving both mu and delta receptors. Activation of the former in heroin abusers produces sedation and overstimulation, lack of vigilance, and possibly fear. These effects cannot be reached with dual inhibitors, and one can speculate that this is related to an increased level of endogenous enkephalins leading to a preferential interaction with delta receptors for both binding and anatomical reasons. 

Figure 21.5 Mechanisms of opioid analgesia at the spinal level. Action potentials in nociceptive afferent fibres invade the terminal and by opening calcium channels (L, N and P-type) cause the release of glutamate and peptides that further transmit pain subsequent to activation of their postsynaptic receptors. Presynaptic opioid receptor activation (mu- and delta-mediated effects have been most clearly shown) opens potassium channels which hyperpolarise the terminal, so reducing transmitter release and inhibiting the postsynaptic neuron...

Thomas, J.B., Herault, X.M., Rothman, R.B., Atkinson, R.N., Burgess, J.P., Mascarella, S.W., Dersch, C.M., Xu, H., Flippen-Anderson, J.L., George, C.F., Carroll, F.I. Factors influencing agonist potency and selectivity for the opioid delta receptor are revealed in structure-activity relationship studies of the 4-[(N-substituted-4-piperidinyl)arylamino]-N,N-diethylbenzamides, J. Med. Chem. 2001, 44, 972-987. 

Rady, J.J., A.E. Takemori, P.S. Portoghese, and J.M. Fujimoto, Supraspinal delta receptor subtype activity of heroin and 6-monoacetyhnorphine in Swiss Webster mice, Life Sci., 55(8), 603-609, 1994. 

Scientific research has shown that methadone and other opiates have specific areas, or sites, that they attach to in order to exert their influence on the brain and body. These sites, called receptors, are classified as mu, delta, and kappa, depending on what body functions they influence. Opiate activation of mu and delta receptors seems to influence mood, respiration, pain, blood pressure, and gastrointestinal functions. Kappa receptors appear to be more involved in the perception and aversion to pain. The degree of methadone s effect on these receptors can vary widely between individuals, however, there are certain effects that are almost universal. 

All opioids produce their effect by activating one or more of the three types of receptors. Thus analgesia involves the activation of the mu receptors that are located mainly at supraspinal sites and kappa receptors in the spinal cord delta receptors may also be involved but their relative contribution is unclear. Nevertheless, the actions of the opioids on these receptors is complex, as there is evidence that the same substance may act as a full agonist, or as an antagonist at different sites within the brain. 

Many of the areas found to be high in delta receptors are part of the limbic system associated with the control of emotion and reward behavior. Such areas include olfactory tubercle, the nucleus accumbens, and the amygdala. However, recent demonstrations have shown that delta agonists may have antidepression activity in the forced swimming test [24 Chap. 20], and the lack of abuse or self-administrative activity in monkeys [25 Chap. 23] may point to the unknown functions of delta receptors in the limbic system. 

Figure 1 Important residues for delta receptor structure-activity. (A) Lateral view of a 3D model of the human delta opioid receptor. This model is based on x-ray crystallographic data from rhodopsin [91]. Helices are indicated as ribbons, side chains of amino acids implicated in binding (dark gray) or both binding and activation (light gray) are shown as sticks. Hydrophilic bonds are shown as dotted lines. (B) Position of important residues along the human delta opioid receptor sequence [34] using the same color code. (C) Scheme representing the receptor viewed from the extracellular face using the same color code.

The selectivity of currently used delta agonists may not be sufficient to avoid mu receptor activation in vivo. As an example, one study showed that DPDPE (selectivity delta/mu 100-fold) injected either ICV or ITH was less active in the mu receptor mutant than deltorphin (selectivity mu/delta 10,000-fold) [60]. This suggests that, in WT mice the less delta selective compound recruits mu receptors to produce analgesia in the tail flick and hot plate tests under their experimental conditions. 

Delta receptors nevertheless mediate some delta agonist induced analgesia, as suggested by reduced DPDPE and deltorphin activity in the DOR mutant after ITH applications [52], or enhanced antinociceptive activity in MOR mutants subjected to CFA inflammation [65]. Delta receptors also depress respiratory neurons in slice preparations [66] and mediate SNC80-evoked convulsions [67]. 

Biological activity Compound Delta receptor KO (52) Mu receptor KO... 

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