Effect on nociception of intracerebroventricular administration of low doses of neuropefitde y in mice

Mellado, Manuel; Gibert-Rahola, J.; Chover, A.J.; Micó, Juan Antonio

doi:10.1016/0024-3205(96)00244-5

Cited by 19 publications

(4 citation statements)

References 22 publications

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“…Similarly, NPY has been shown to play a neuromodulatory role in pain transmission. The analgesic activity of NPY-dPEG 24 in the formalin assay was consistent with the previous report that NPY was active in the acute phase in this test following icv administration . NPY reduces signs of inflammatory and neuropathic pain .…”

Section: Discussionsupporting

confidence: 91%

“…The analgesic activity of NPY-dPEG 24 in the formalin assay was consistent with the previous report that NPY was active in the acute phase in this test following icv administration. 84 NPY reduces signs of inflammatory and neuropathic pain. 60 NPY also produces a long-lasting tonic inhibition of spinal nociception mediated by both Y1 and Y2 receptors.…”

Section: ■ Discussionmentioning

confidence: 99%

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Incorporation of Monodisperse Oligoethyleneglycol Amino Acids into Anticonvulsant Analogues of Galanin and Neuropeptide Y Provides Peripherally Acting Analgesics

Zhang¹,

Klein²,

Metcalf³

et al. 2013

Mol. Pharmaceutics

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Delivery of neuropeptides into the central and/or peripheral nervous systems supports development of novel neurotherapeutics for the treatment of pain, epilepsy and other neurological diseases. Our previous work showed that the combination of lipidization and cationization applied to anticonvulsant neuropeptides galanin (GAL) and neuropeptide Y (NPY) improved their penetration across the blood-brain barrier yielding potent antiepileptic lead compounds, such as Gal-B2 (NAX 5055) or NPY-B2. To dissect peripheral and central actions of anticonvulsant neuropeptides, we rationally designed, synthesized and characterized GAL and NPY analogues containing monodisperse (discrete) oligoethyleneglycol-lysine (dPEG-Lys). The dPEGylated analogues Gal-B2-dPEG(24), Gal-R2-dPEG(24) and NPY-dPEG(24) displayed analgesic activities following systemic administration, while avoiding penetration into the brain. Gal-B2-dPEG(24) was synthesized by a stepwise deprotection of orthogonal 4-methoxytrityl and allyloxycarbonyl groups, and subsequent on-resin conjugations of dPEG(24) and palmitic acids, respectively. All the dPEGylated analogues exhibited substantially decreased hydrophobicity (expressed as logD values), increased in vitro serum stabilities and pronounced analgesia in the formalin and carrageenan inflammatory pain assays following systemic administration, while lacking apparent antiseizure activities. These results suggest that discrete PEGylation of neuropeptides offers an attractive strategy for developing neurotherapeutics with restricted penetration into the central nervous system.

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Section: Discussionsupporting

confidence: 91%

Section: ■ Discussionmentioning

confidence: 99%

Incorporation of Monodisperse Oligoethyleneglycol Amino Acids into Anticonvulsant Analogues of Galanin and Neuropeptide Y Provides Peripherally Acting Analgesics

Zhang¹,

Klein²,

Metcalf³

et al. 2013

Mol. Pharmaceutics

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“…Although nerve injury has been shown to increase NPY expression in the dorsal root ganglia, spinal cord, and dorsal column nuclei (Li et al, 1999), the role of this peptide in the modulation of nociception has remained inconclusive. Pharmacological neuropeptide Y (NPY) has been reported as both antinociceptive and pronociceptive (Hua et al, 1991;Jolicoeur et al, 1991;Heilig et al, 1992;Broqua et al, 1996;Mellado et al, 1996;Taiwo and Taylor, 2002), often with biphasic dose-effect curves (Xu et al, 1994(Xu et al, , 1999. Excitatory effects of NPY have been observed in dorsal root ganglion (DRG) cells taken from rats with nerve injury (Abdulla and Smith, 1999).…”

mentioning

confidence: 99%

Selective Mediation of Nerve Injury-Induced Tactile Hypersensitivity by Neuropeptide Y

et al. 2002

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Prevention of nerve injury-induced tactile, but not thermal, hypersensitivity is achieved by ipsilateral lesions of the dorsal columns or lidocaine microinjection into the nucleus gracilis (n. gracilis). These and other data support the possibility that tactile hyperresponsiveness after nerve injury may be selectively mediated by a low-threshold myelinated fiber pathway to the n. gracilis. Here we identify a transmitter that might selectively mediate such injury-induced tactile hypersensitivity. Neuropeptide Y (NPY), normally not detected in the dorsal root ganglion (DRG) or in the n. gracilis of rats, became markedly upregulated at both sites and in the spinal cord after spinal nerve injury. Injury-induced NPY-IR occurred predominately in large-diameter DRG cells, and the NPY-IR in the n. gracilis was blocked by dorsal rhizotomy or dorsal column lesion. NPY microinjection into the n. gracilis of uninjured rats elicited reversible tactile, but not thermal, hypersensitivity only in the ipsilateral hindpaw. Administration of anti-NPY antiserum, but not control serum or preabsorbed serum, into the n. gracilis ipsilateral to nerve injury reversed tactile, but not thermal, hypersensitivity. Similarly, microinjection of the NPY antagonists NPY(18-36) and (R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N2-(diphenylacetyl)-argininamide trifluoroacetate, into the n. gracilis ipsilateral to the injury reversed tactile, but not thermal, hypersensitivity. Antagonist administration into the contralateral n. gracilis had no effect on injury-induced hypersensitivity. These data suggest the selective mediation of nerve injury-induced tactile hypersensitivity by upregulated NPY via large fiber input to n. gracilis. Selective reversal of injury-induced tactile allodynia by NPY receptor antagonists would have significant implications for human neuropathic conditions.

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“…The contribution of NPY to neuropathic pain behavior appears to be very complex. Exogenous NPY largely exerts analgesic effects on nociceptive behaviors and reflexes independently to the route; spinal intrathecal injection (Hua et al, 1991;Taiwo and Taylor, 2002;Intondi et al, 2008), intracerebroventricular injection (Broqua et al, 1996;Mellado et al, 1996), and intracisternal injection at the medulla level (Jung et al, 2009). However, some studies have reported pronociceptive effects of exogenous NPY in dose-dependent and/or receptor-dependent manners (Xu et al, 1994(Xu et al, , 1999.…”

Section: Introductionmentioning

confidence: 94%

A potential anti-allodynic mechanism of GDNF following L5 spinal nerve ligation; Mitigation of NPY up-regulation in the touch sense pathway

Fukuoka

Noguchi

2015

Neuroscience

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Effect on nociception of intracerebroventricular administration of low doses of neuropefitde y in mice

Cited by 19 publications

References 22 publications

Incorporation of Monodisperse Oligoethyleneglycol Amino Acids into Anticonvulsant Analogues of Galanin and Neuropeptide Y Provides Peripherally Acting Analgesics

Incorporation of Monodisperse Oligoethyleneglycol Amino Acids into Anticonvulsant Analogues of Galanin and Neuropeptide Y Provides Peripherally Acting Analgesics

Selective Mediation of Nerve Injury-Induced Tactile Hypersensitivity by Neuropeptide Y

A potential anti-allodynic mechanism of GDNF following L5 spinal nerve ligation; Mitigation of NPY up-regulation in the touch sense pathway

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