N receptor

A critical cellular response to opiates is the potentiation of K+ currents [42]. Stimulation of n receptors in neurons causes an increase in K+ conductance and a reduction in cell firing. Prolonged administration of fi agonists diminishes the ability of the opiates to increase K+ conductance to inhibit neuronal firing and pain transmission is no longer attenuated. 

Brady-Kalnay, S., Rimm, D. and Tonks, N. Receptor protein tyrosine phosphatase PTPm associates with cadherins and catenins in vivo. J. Cell Biol. 130 977-986,1995. 

Action duration of GABAa opening, leading to CP current Stimulates GABA inhibits NMDA Inhibits NMDA and opioid n receptors (stimulates k, and S) Stimulates GABA... 

Interaction at the K-receptor increases the sedative effects of the drugs. The euphoric effects are due to interaction with the jL-receptor. The dysphoric and psychotomimetic side effects of the drugs are attributed to interaction at the n-receptor. 

The principal effects of opioid analgesics with affinity for n- receptors are on the CNS the more important ones include analgesia, euphoria, sedation, and respiratory depression. With repeated use, a high degree of tolerance occurs to all of these effects (Table 31-3). 

Specialized cells such as neurons and muscle cells are electrically excitable and controlled by transmitter and modulator substances. Chemicals can affect the regulation of the activities of such cells. This can occur by (i) alterations in a neurotransmitter, (n) receptor function, (Hi) intracellular signal transduction, or (iv) signal-terminating processes. 

The striatum, the nucleus accumbens, the hippocampus, the lateral nucleus of the hypothalamus, the habenula, the interpeduncular nucleus, the nucleus of the tractus soli-tarius, the raphe nuclei and the medulla oblongata are rich in tachykinin NK1 receptors (Otsuka and Yoshioka, 1993). The predominant expression of N receptors within the spinal dorsal horn is consistent with the assumption that SP and NKA are important messengers here (Bleazard et al., 1994). The distribution of NKi receptors in the peripheral nervous system and in the gut are discussed elsewhere (McLean, 1996 Quartara and Maggi, 1997, 1998). 

Further experimental evidence for the involvement of SP in pain perception came from knock-out animals. Mice, in which the preprotachykinin A gene was disrupted, showed significantly reduced responses in tests that involved more intense noxious stimuli (Cao et al., 1998). De Felipe et al. (1998) disrupted the N receptor, and found the characteristic amplification ( wind up ) and intensity coding of nociceptive reflexes to be absent. NK receptor knockout mice show no changes in acute nociception tests. In contrast, SP and NKi receptor knock-out mice show reduction in responses to inflammatory stimuli. Nerve injury-induced mechanical but not thermal hyperalgesia is attenuated in NKi receptor knock-out mice, when inducing chronic neuropathic pain by unilateral ligation of the L5 spinal nerve (Mansikka et al., 2000). 

There are probably several processes that contribute to the total desensihzation process and these may be directed homologously (to ow n receptor) or heterologously (to other receptor). Additionally, the influences may be directed at the receptor itself and affect only that receptor, i.e, specific desensitization, or may affect other receptor processes as well, i.e., nonspecific desensitization. 

After intravenous injection, clonidine produces a brief rise in blood pressure followed by more prolonged hypotension. The pressor response is due to direct stimulation of -adrenoceptors in arterioles. The drug is classified as a partial agonist at n-receptors because it also inhibits pressor effects of other a-agonists. 

Morphine antinociception is mediated predominantly by n receptors. Its enhancement by zl9-THC, however is through activation of k and S receptors... 

Figure 7.30 Mode of action of Cry toxins. (a,b) Crystals are solubilized and activated to give rise to the monomeric toxin, (c) The toxin monomer binds in cadherin receptor, followed by proteolytic cleavage of helix a-1. (d) The tetramer is formed by inter monomeric contacts, (e) The toxin oligomer binds to the aminopeptidase-N receptor (APN receptor). The APN receptor and oligomeric Cry toxin localize to lipid rafts, (f) Following a conformational change, the oligomer inserts into membrane, forming a tetrameric pore. (From Bravo et al., in Comprehensive Molecular Insect Science, Gilbert, L.I., Iatrou, K., and Gill, S.S., Eds., Vol. 6, Elsevier, London, 2005, p. 175. With permission.)...

Althov both type I and II receptors have a kinase domain, eadi has a different function. Whereas the type I receptor kinase phosphorylates the substrates, the SMADs, the type n receptor kinase autophosphorylates itself and the type I receptor. Only die type I receptor in the I/II heterodimer interacts with R-SMADs. No TGF-p responses have been found in cells lacking type I receptors, althot h the type II receptors should be able to signal, because they have a functional kinase, leaving open the possibility that type II... 

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