Opiate receptors kappa

P.L. Wood, S.E. Charleson, D. Lane and R.L. Hudgin, Multiple opiate receptors differential binding of mu, kappa and delta agonists. Neuropharmacology, 20 (1981) 1215-1220. 

Clark JA, Liu L, Price M, Hersh B, Edelson M, Pasternak GW. Kappa opiate receptor multiplicity evidence for two U50,488-sensitive k3 subtypes and a novel k3 subtype. J Pharmacol Exp Ther 1989 251 461-468. 

Pfeiffer A., Brandt V., Herz A. Psychotomimesis mediated by kappa opiate receptors. Science. 233 774, 1986. 

If opiates are such addictive and potentially lethal compounds, why does the body respond to them As with the cannabinoids (Chapter 7), it has been discovered that the body and brain possess numerous opiate-specific receptor sites. As many as nine receptor subtypes have been identified, with three of them being the most important p (mu), k (kappa) and 8 (delta). The finding that the distribution of opiate receptors did not parallel the distribution of any known neurotransmitter prompted the search for and identification of a number of endogenous compounds specific to these receptors. These enkephalins and endorphins are manufactured within the brain and other body systems (especially the gut and intestines) and form the body s natural response to pain. They appear to be produced in bulk chains of amino acids called polypeptides , with each active neurotransmitter being composed of around five amino acid molecules. These active neurotransmitters are subsequently cleaved from the larger polypeptides at times of demand for example, it has been demonstrated that the plasma levels of these active compounds rise during childbirth, traumatic incidents and vigorous physical exercise. 

Wang J, Johnson P, Wu J, Wang W, Uhl G. Human kappa opiate receptor second extracellular loop elevates dynor-phiris affinity for human mu/kappa chimeras. J Biol Chem 1994 269 25966-25969. 

Several opiate receptors have been identified on cells of the nervous systems of animals and humans, with mu (p), kappa (k), and gamma (y) subtypes being predominant. These classical opiate receptors are G- protein coupled 7-transmembrane molecules.27 Opiates predominantly affect immune responses directly by ligation of p, k, and y opiate receptors, as well as non-classical opiate-like receptors, on immune cells and indirectly by binding to receptors on CNS cells. Studies conducted in vitro with opiate-treated immune cells demonstrated receptor-mediated reduced phagocytosis, chemotaxis and cytokine and chemokine production. These effects are linked to modulation of host resistance to bacterial, protozoan, viral and fungal infections using animal models, cell lines and primary cells. 

The plant alkaloids mimic the endogenous peptides enkephalins and endorphins (Chapter 12), which meditate nociception and sleep. There are three types of widely distributed opiate receptors. Mu receptors are concentrated in neocortex, striatum, thalamus, hippocampus, amygdala and spinal cord, delta receptors in neocortex and amydala, and kappa receptors in striatum, amygdala and hypothalamus (Mansour et al., 1988). 

Wood, P.L. Multiple opiate receptors support for unique mu, delta and kappa sites, Neuropharmacology 1982, 21, 487-497. 

Opiates act on a variety of receptors. The three most important subtypes are the mu, delta, and kappa opiate receptors (Fig. 13—25). The brain makes its own endogenous opiate-like substances, sometimes referred to as the brain s own morphine. They are peptides derived from precursor proteins called pro-opiomelanocortin (POMC), proenkephalin, and prodynorphin. Parts of these precursor proteins are cleaved off to form endorphins or enkephalins, stored in opiate neurons, and presumably released during neurotransmission to mediate endogenous opiate-like actions (Fig. 13-25). However, the precise number and function of endogenous opiates and their receptors and their role in pain relief and other central nervous system (CNS) actions remain largely unknown. 

Buprenorphine is a semi-synthetic, partial mu-agonist, highly lipophilic, opioid drug. Because it is a partial agonist, when buprenorphine competes with morphine or heroin for mu-receptors it can reduce their maximum effect. Buprenorphine binds strongly to mu and kappa opiate receptors it associates with the mu-receptor slowly (30 minutes), but with high affinity, low intrinsic activity and slow and incomplete dissociation. The slow dissociation from the receptor probably limits the intensity of withdrawal by preventing the rapid... 

Royston MC, Slater P, Simpson MD, Deakin JF. 1991. Analysis of laminar distribution of kappa opiate receptor in human cortex Comparison between schizophrenia and normal. J Neurosci Methods 36 145-153. 

Kappa opiate receptor agonists including 3-azabicyclo[3.1.0]hexane derivatives, (III), and piperazine derivatives, (IV), prepared by Banks (5) and Kruse (6), respectively, were effective in treating pruritic disorders. 

Zadina JE, Kastin AJ, Ge L-J, Hackler L (1994) Mu, delta, and kappa opiate receptor binding of Tyr-MIF-1 and of Tyr-W-MIF-1, its active fragments, and two potent analogs. Life Sci 55 PL461-PL466... 

Heroin s primary toxic principle is its profound ability to depress the central nervous system (CNS). Opioid analgesics bind with stereospecific receptors at many sites within the CNS. Heroin, similar to other opioids, exerts its pharmacologic effect by acting at mu, kappa, and delta receptors in the brain. Although the precise sites and mechanisms of action have not been fully determined, alterations in the release of various neurotransmitters from afferent nerves sensitive to painful stimuli may be partially responsible for the analgesic effect. Activities associated with the stimulation of opiate receptors are analgesia, euphoria, respiratory depression, miosis, and reduced gastrointestinal motility. 

Isom et al. mentioned endogenous generation of CN and the possibility that CN may function as a neuromodulator in a manner similar to nitric oxide. Brain CN levels are increased by hydromorphone and the effect is blocked by naloxone. Undifferentiated rat pheochromocytoma cells also show increased CN production in response to hydromorphone or morphine. Since PC 12 cells have mainly kappa opiate receptors and no mu receptors, hydromorphone probably acts through kappa receptors to increase CN release. ... 

---