Central nervous system opioids

In addition to the weU-defined opioid systems in the central nervous system, the three opioid peptides and their precursor mRNA have also been identified in peripheral tissues. ( -Endorphin is most abundant in the pituitary, where it exists in corticotroph cells with ACTH in the anterior lobe and in melanotroph cells with MSH in the intermediate lobe (59). Enkephalin and pre-pro-enkephalin mRNA have been identified in the adrenal medulla (60) and this has been the source of material for many studies of pro-enkephalin synthesis and regulation. Pre-pro-enkephalin mRNA has also been identified in the anterior and posterior lobes of the pituitary (61). mRNA for all three opioid precursors has been identified in the reproductive system (62—64). POMC... 

Endogenous opioid peptide released both in the central nervous system and in other apparatuses of the body that have many regulatory functions, including inhibition of pain transmission. 

Carpentier PA, Duncan DS, Miller SD (2008) GUal toU-hke receptor signaling in central nervous system infection and autoimmunity. Brain Behav Immun 22 140-147 Carr DJ, Serou M (1995) Exogenous and endogenous opioids as biological response modifiers. Immunopharmacology 31 59-71... 

Sheng WS, Hu S, Gekker G, Zhu S, Peterson PK, Chao CC (1997) Immunomodulatory role of opioids in the central nervous system. Arch Immunol Ther Exp (Warsz) 45 359-366 Sheng WS, Hu S, Lokensgard JR, Peterson PK (2003) U50, 488 inhibits HIV-1 Tat-induced monocyte chemoattractant protein-1 (CCL2) production by human astrocytes. Biochem Pharmacol 65 9-14... 

As one might expect, similar interactions between chemokine and opioid systems have been observed in the central nervous system as weU. In 2002, Szabo et al. 

There is a definite trend of bidirectional cross-talk between opioid and chemokine receptors in the central nervous system. In vitro, as well as in vivo studies, have shown desensitization of CXCR4 by MOR and thus prevent the neuroprotective action of this chemokine. Although the precise molecular mechanism underlying this cross-talk is still under investigation, based on the evidences in literature several possible pathways can be expected to act independently or in concert and lead to the deficit of CXCR4 function. Our studies have shown that p opioids can increase the brain levels of FHC which can subsequently block CXCR4 signaling. Eurther studies... 

Henriksen G, Willoch P (2008) Imaging of opioid receptors in the central nervous system. Brain 131 1171-1196... 

Severe pain should be treated with an opioid such as morphine, hydromorphone, methadone, or fentanyl. Moderate pain can be treated effectively in most cases with a weak opioid such as codeine or hydrocodone, usually in combination with acetaminophen. Meperidine should be avoided owing to its relatively short analgesic effect and its toxic metabolite, normeperidine. Normeperidine may accumulate with repeated dosing and can lead to central nervous system side effects including seizures. 

The three prototype mixed p agonist/S antagonists described in this chapter have excellent potential as analgesics with low propensity to produce tolerance and dependence. The pseudotetrapeptide DIPP-NH2[ ] has already been shown to produce a potent analgesic effect, less tolerance than morphine, and no physical dependence upon chronic administration. In preliminary experiments, the tetrapeptides DIPP-NH2 and DIPP-NH2[T] were shown to cross the BBB to some extent, but further structural modifications need to be performed in order to improve the BBB penetration of these compounds. The Tyr-Tic dipeptide derivatives can also be expected to penetrate into the central nervous system because they are relatively small, lipophilic molecules. In this context, it is of interest to point out that the structurally related dipeptide H-Dmt-D-Ala-NH-(CH2)3-Ph (SC-39566), a plain p-opioid agonist, produced antinociception in the rat by subcutaneous and oral administration [72], As indicated by the results of the NMR and molecular mechanics studies, the conformation of the cyclic p-casomorphin analogue H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-] is stabilized by intramolecular hydrogen bonds. There-... 

Simonin F., Gaveriaux-Ruff C., Befort K. et al. k-Opioid receptor in humans cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system. Proc. Natl. Acad. Sci. U.S.A. 92 7006, 1995. 

Ding Y, Kaneko T, Nomura S, Mixuno N. Immunohistochemical localization of mu opioid receptors in the central nervous system of the rat. J Comp Neurol 1996 367 375-402. 

Another site of action for opioids is through the regulatory actions of the central nervous system (CNS) on the immune system. Substantial evidence supports the existence of a complex, bidirectional link between the CNS and the immune system (e.g., [65]). Experimental evidence indicates that morphine s immunomodulatory effects involve central opioid receptors. An initial study by Shavit and colleagues [12] found that systemic administration of morphine, but not N-methylmorphine (a form of morphine which does not readily penetrate the blood-brain barrier), produces a naltrexone-reversible suppression of splenic natural killer cell activity in the rat. That same study showed that intracerebroventricular (icv) administration of morphine dose-dependently suppresses... 

Fecho, K. et al., Assessment of the involvement of central nervous system and peripheral opioid receptors in the immunomodulatory effects of acute morphine treatment in rats, J. Pharmacol. Exp. Ther., 276, 626, 1996a. 

The classic endogenous opioid peptides are derived from one of three families of precursors proopiomelanocortin (POMC), pro-dynorphin, and pro-enkephalin. Many active opioid peptides are derived from these three, but the best known are )S-endorphin, enkephalin, and dynorphin. POMC is produced by nuclei in the hypothalamus and medulla (Khachaturian et al. 1985 Watson et al. 1978 Bloom et al. 1978). Enkephalin and dynorphin neurons are distributed to all levels of the central nervous system (Hokfelt et al. 1977 Khachaturian et al. 1983 Sar et al. 1978 Khachaturian et al. 1985). 

Tramadol is an opioid analgesic and when given to patients who are also receiving imipramine (a tricyclic antidepressant), there is an increased risk of central nervous system toxicity. The risk of occurrence of sedation is increased. 

Analgesics are divided into two groups opioids (morphine-like substances), which predominantly influence the central nervous system (CNS) and nonopioids (nonsteroidal antiinflammatory or fever-reducing drugs—NSAID), which act predominantly on the peripheral nervous system. 

The most potent and pervasive pain suppression system appears to be provided by endogenous opioids, particularly methionine encephalin and beta endorphin. These opioids and their receptors are widely distributed at several levels in the central nervous system (Mansour et al., 1988). Enkephalins appear to control the responses of dorsal horn neurons and may also modulate pain... 

Codeine phosphate is still used for diarrhea predominantly based on hypermotility but the longer-acting loperamide is more convenient and has less central nervous system effects. Codeine has an exceptionally low affinity for opioid receptors and its effects are due to the fact that it is converted for approximately 10% to morphine. The active metabolite of morphine, morphine-6-glucuronide, may also accumulate during repeated administration of codeine to patients with impaired renal function. 

Potent opioids act through opioid receptors in the central nervous system where they inhibit the transport of pain impulses. They are mostly used for treatment of malignant cancer pain and for post-operative pain. Severe, long-term non-malignant pain, e.g. in ischaemic leg ulcers, sometimes necessitates the use of opioids. The risk of treatment discontinuation due to adverse reactions is high. 

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