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Maszczynska, Iwona; Lipkowski, Andrzej W.; Carr, Daniel B.; Kream, Richard M.

doi:10.1023/a:1008890726179

Cited by 2 publications

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“…In light of the established literature indicating that SP-and opioid-expressing neurons presumably mediate opposite physiological effects at the spinal level, investigators have tended to overlook the role of SP and SP receptors (SPRs) in the regulation of endogenous opioid systems (10)(11)(12)(13)(14), particularly in the area of analgesic responsiveness. Previous pharmacological data from our group strongly suggest that SP released in the dorsal horn plays an important role in antinociception by regulating analgesic activity of the postsynaptic opioid systems (15,16). In particular, we demonstrated that low doses of SP, when coadministered with marginally effective doses of morphine sulfate (MS) into the rat subarachnoid space, produce a markedly enhanced analgesic response.…”

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confidence: 68%

A substance P-opioid chimeric peptide as a unique nontolerance-forming analgesic

Foran

Carr

Lipkowski

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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To elucidate mechanisms of acute and chronic pain, it is important to understand how spinal excitatory systems influence opioid analgesia. The tachykinin substance P (SP) represents the prototypic spinal excitatory peptide neurotransmitter͞neuromodulator, acting in concert with endogenous opioid systems to regulate analgesic responses to nociceptive stimuli. We have synthesized and pharmacologically characterized a chimeric peptide containing overlapping NH2-and COOH-terminal functional domains of the endogenous opioid endomorphin-2 (EM-2) and the tachykinin SP, respectively. Repeated administration of the chimeric molecule YPFFGLM-NH2, designated ESP7, into the rat spinal cord produces opioid-dependent analgesia without loss of potency over 5 days. In contrast, repeated administration of ESP7 with concurrent SP receptor (SPR) blockade results in a progressive loss of analgesic potency, consistent with the development of tolerance. Furthermore, tolerant animals completely regain opioid sensitivity after post hoc administration of ESP7 alone, suggesting that coactivation of SPRs is essential to maintaining opioid responsiveness. Radioligand binding and signaling assays, using recombinant receptors, confirm that ESP7 can coactivate -opioid receptors (MOR) and SPRs in vitro. We hypothesize that coincidental activation of the MOR-and SPR-expressing systems in the spinal cord mimics an ongoing state of reciprocal excitation and inhibition, which is normally encountered in nociceptive processing. Due to the ability of ESP7 to interact with both MOR and SPRs, it represents a unique prototypic, anti-tolerance-forming analgesic with future therapeutic potential.T he neuropeptide substance P (SP) and endogenous opioids are intimately involved in the regulation of acute and chronic pain transmission (1-6). Overlapping distributions of SP-and opioid-containing neurons, as well as their corresponding G protein-coupled receptors, within the superficial dorsal horn of the spinal cord suggest major SP͞opioid functional interactions (7-9). The superficial dorsal horn is an important site of functional integration and transmission of nociceptive input. Here neuronal signaling is mediated by both SP and excitatory amino acids released from primary afferent terminals with further modulation by opioid peptides originating from secondorder spinal cord neurons. In light of the established literature indicating that SP-and opioid-expressing neurons presumably mediate opposite physiological effects at the spinal level, investigators have tended to overlook the role of SP and SP receptors (SPRs) in the regulation of endogenous opioid systems (10-14), particularly in the area of analgesic responsiveness. Previous pharmacological data from our group strongly suggest that SP released in the dorsal horn plays an important role in antinociception by regulating analgesic activity of the postsynaptic opioid systems (15,16). In particular, we demonstrated that low doses of SP, when coadministered with marginally effective doses of morphine sulfa...

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mentioning

confidence: 68%

A substance P-opioid chimeric peptide as a unique nontolerance-forming analgesic

Foran

Carr

Lipkowski

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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“…administration of compound 69 elicited bell-shaped antinociceptive effects with maximum efficacy at 0.2 mg/kg. This phenomenon was also observed when peptidic twin drugs [107,108] or coadministration of both morphine and SP [140,141] were applied. The analgesic effects produced by 69 were attenuated by L733060 (SP antagonist) or nor-BNI (k antagonist).…”

Section: Opioid and Substance P Pharmacophoresmentioning

confidence: 66%

“…SP is known to enhance analgesia and to inhibit tolerance induced by opioids [108,140,141]. Based on such background information, several peptidic twin drugs with opioid and SP pharmacophores have been reported [108][109][110][111][112].…”

Section: Opioid and Substance P Pharmacophoresmentioning

confidence: 99%

Twin and Triplet Drugs in Opioid Research

Fujii

2010

Topics in Current Chemistry

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Twin and triplet drugs are defined as compounds that contain respectively two and three pharmacophore components exerting pharmacological effects in a molecule. The twin drug bearing the same pharmacophores is a "symmetrical twin drug", whereas that possessing different pharmacophores is a "nonsymmetrical twin drug." In general, the symmetrical twin drug is expected to produce more potent and/or selective pharmacological effects, whereas the nonsymmetrical twin drug is anticipated to show both pharmacological activities stemming from the individual pharmacophores (dual action). On the other hand, nonsymmetrical triplet drugs, which have two of the same pharmacophores and one different moiety, are expected to elicit both increased pharmacological action and dual action. The two identical portions could bind the same receptor sites simultaneously while the third portion could bind a different receptor site or enzyme. This review will mainly focus on the twin and triplet drugs with an evaluation of their in vivo pharmacological effects, and will also include a description of their pharmacology and synthesis.

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Cited by 2 publications

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A substance P-opioid chimeric peptide as a unique nontolerance-forming analgesic

A substance P-opioid chimeric peptide as a unique nontolerance-forming analgesic

Twin and Triplet Drugs in Opioid Research

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