Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study compared the antinociceptive properties of systemic administration of selective, non-peptidergic antagonists at neurokinin (NK1 and NK2) receptors to those of other classes of antinociceptive agent. (All doses are in mg/kg.) In mice, the NK1 antagonist, CP 99,994, preferentially (inhibitory dose50 (ID50) = 4.4) inhibited the late phase (LP) as compared to the early phase (EP) (16.1) of formalin-induced licking (FIL). A high dose (17.6) elicited ataxia in the rotarod test. Acetic acid-induced writhing was reduced at intermediate doses (10.0) whereas the tail-flick (TF) response to thermal and mechanical stimuli was inhibited only at high doses (22.7 and 17.7, respectively). Modulation of stimulus intensity did not modify the influence of CP 99,994 upon the response to heat. A similar pattern of data was acquired with RP 67,580, although this NK1 antagonist more potently inhibited writhing (2.8). In contrast, RP 68,651, the inactive isomer of RP 67,580, neither reduced the LP of FIL nor modified writhing indicating that these actions of RP 67,580 were stereospecific. Three further NK1 antagonists, SR 140,333, WIN 51,708 and WIN 62,577, likewise inhibited the LP of FIL and failed to modify the TF response at non-ataxic doses. Further, SR 140,333 (0.5) and WIN 51,708 (1.4) were potent ligands in the writhing procedure. The NK2 antagonist, SR 48,966, mimicked NK1 antagonists in preferentially inhibiting the LP (7.7) as compared to the EP (26.9) of FIL. Further, only at doses higher than those evoking ataxia (20.9) did SR 48,968 modify the TF response (36.5 and 32.0 for heat and pressure, respectively). However, it differed to NK1 antagonists in being inactive in the writhing test (> 40.0). In comparison to these NK1 and NK2 antagonists, the mu-opioid agonists (morphine and fentanyl) and kappa-opioid agonists (enadoline and U 69,593) equipotently inhibited all nociceptive responses at doses not provoking ataxia. While the glycine B receptor partial agonist, (+)-HA 966, selectively blocked the LP of FIL and did not evoke ataxia, the NMDA receptor channel blocker, (+)-MK 801, elicited antinociception only at doses close to those provoking ataxia. Finally, the NSAIDs, indomethacin and ibuprofen, the BK2 antagonist, Hoe 140 and the nitric oxide synthase (NOS) inhibitors, L-NAME and 7 nitroindazole, inhibited the LP (but not the EP) of FIL and (except for L-NAME) also reduced writhing: in contrast, they did not evoke ataxia and were inactive in the TF procedures.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Antinociceptive profiles of non-peptidergic neurokinin1 and neurokinin2 receptor antagonists: a comparison to other classes of antinociceptive agent. 765 44

The tachykinin receptor antagonists (3aR,7aR)-7,7-diphenyl-2(1-imino-2-(2-methoxyphenyl/ethyl)++ +perhydroisoindole) (RP 67580) and (+)-(2S-3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994), which act selectively at neurokinin (NK)1 receptors, inhibited the early phase of formalin-induced pain in mice. Although (+)-(1-hydroxy-3-aminopyrrolidine-2-one) ((+)-HA966), a partial agonist at glycine B receptors, was inactive alone, it potentiated the actions of RP 67580 (but not its inactive stereoisomer, RP68651) and CP-99,994. In its presence, the dose-response curve for RP 67580 was dose-dependently shifted to the left. In contrast, (+)-HA966 did not modify the induction of ataxia by RP 67580 and CP-99,994. These data suggest that co-administration of partial agonists at glycine B receptors may improve the antinociceptive potency and 'therapeutic window' of tachykinin NK1 receptor antagonists.
 ...
PMID:The glycine B receptor partial agonist, (+)-HA966, enhances induction of antinociception by RP 67580 and CP-99,994. 801 34

We previously identified four missense mutations in the prodynorphin gene that cause human neurodegenerative disorder spinocerebellar ataxia type 23 (SCA23). Three mutations substitute Leu(5), Arg(6), and Arg(9) to Ser (L5S), Trp (R6W) and Cys (R9C) in dynorphin A(1-17) (Dyn A), a peptide with both opioid activities and non-opioid neurodegenerative actions. It has been reported that Dyn A administered intrathecally (i.t.) in femtomolar doses into mice produces nociceptive behaviors consisting of hindlimb scratching along with biting and licking of the hindpaw and tail (SBL responses) through a non-opioid mechanism. We here evaluated the potential of the three mutant peptides to produce similar behaviors. Compared to the wild type (WT)-peptide, the relative potency of Dyn A R6W, L5S and R9C peptides for SBL responses was 50-, 33- and 2-fold higher, and Dyn A R6W and L5S induced the SBL responses at a 10-30-fold lower doses. Dyn A R6W was the most potent peptide. The SBL responses induced by Dyn A R6W were dose dependently inhibited by morphine (i.p.; 0.1-1 mg/kg) or MK-801, an NMDA ion channel blocker (i.t. co-administration; 5-7.5 nmol). CP-99,994, a tachykinin NK1 receptor antagonist (i.t. co-administration; 2 nmol) and naloxone (i.p.; 5 mg/kg) failed to block effects of Dyn A R6W. Thus, similarly to Dyn A WT, the SBL responses induced by Dyn A R6W may involve the NMDA receptor but are not mediated through the opioid and tachykinin NK1 receptors. Enhanced non-opioid excitatory activities of Dyn A mutants may underlie in part development of SCA23.
 ...
PMID:Non-opioid nociceptive activity of human dynorphin mutants that cause neurodegenerative disorder spinocerebellar ataxia type 23. 2253 88