Transient allodynia pain models in mice for early assessment of analgesic activity.
OBJECTIVE
The most common preclinical models of neuropathic pain involve surgical ligation of sensory nerves, which is especially difficult in mice. Transient models of chemically sensitized allodynia are potentially useful for rapidly characterizing the analgesic profile of compounds and conducting mechanistic studies.


METHODS
Increasing doses of NMDA, sulprostone (an EP1/EP3 prostaglandin receptor agonist) or phenylephrine (an alpha (1) adrenoceptor agonist) were injected intrathecally (i.t.) or i.p., and animals were subsequently assessed for allodynia. The effects of receptor antagonists and analgesic compounds on allodynia were also assessed.


RESULTS
A comparison of total body doses that cause allodynia following spinal or systemic administration indicated that NMDA induces allodynia in the spinal cord while sulprostone and phenylephrine act through a peripheral mechanism. Inhibition of the allodynia with receptor antagonists indicated that each agent induces allodynia by a distinct mechanism. The three models were benchmarked using compounds known to be active in neuropathic pain patients and nerve injury animal models, including gabapentin, amitriptyline and clonidine.


CONCLUSIONS
These transient allodynia models are a useful addition to the toolbox of preclinical pain models. They are simple, rapid and reproducible, and will be especially useful for characterizing the pain phenotype of knockout mice.
Gil
D W
DW
Department of Biological Sciences, Allergan Inc., Irvine, CA, USA. Gil_daniel@allergan.com
Cheevers
C V
CV
Donello
J E
JE
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000588:Amines / Q000494:pharmacology; D000639:Amitriptyline / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D015232:Dinoprostone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D000077206:Gabapentin; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D008297:Male; D008559:Memantine / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology; D016202:N-Methylaspartate / Q000008:administration & dosage*; D010146:Pain / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D017933:Peripheral Nervous System / Q000187:drug effects / Q000378:metabolism; D010656:Phenylephrine / Q000008:administration & dosage; D010879:Piperazines / Q000494:pharmacology; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000187:drug effects / Q000378:metabolism; D058306:Receptors, Prostaglandin E, EP1 Subtype; D015203:Reproducibility of Results; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013127:Spinal Nerves / Q000601:surgery; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D011448:Prostaglandin Antagonists; C545636:Ptger1 protein, mouse; D018340:Receptors, Adrenergic, alpha-1; D016194:Receptors, N-Methyl-D-Aspartate; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D000639:Amitriptyline; C057446:5-methylurapidil; D010656:Phenylephrine; C016767:sulprostone; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D000077206:Gabapentin; D009020:Morphine; D015232:Dinoprostone; D003000:Clonidine; D008559:Memantine
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