Transient allodynia pain models in mice for early assessment of analgesic activity

Abstract

Background and purpose: 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. Experimental approach: Increasing doses of NMDA, sulprostone (an EP1/EP3 prostaglandin receptor agonist) or phenylephrine (an a 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. Key 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 and implications: 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.

A Peripheral Adrenoceptor-mediated Sympathetic Mechanism Can Transform Stress-induced Analgesia into Hyperalgesia

“…30 Peripheral sensitization was elicited with sulprostone, a selective non-inflammatory EP1/EP3 prostaglandin receptor agonist, and tactile allodynia and thermal hyperalgesia were measured. The dose response of sulprostone-induced sensitization to mechanical and thermal stimuli was shifted to the left 10-fold in the α-2A knockout mice (fig.…”

“…30 Briefly, mice were acclimated to brushing of the hind flank with a paintbrush for the first 15 min following intraperitoneal injection of sulprostone or intrathecal injection of NMDA. Starting at 15-min postinjection, the behavioral response to light brushing of the hind flank was scored every 5 min for the time period 15–50 min postinjection.…”

“…The eight time point scores were summed for each animal to generate that animal’s cumulative pain score (maximum pain score of 16). 30 An average of the individual cumulative pain scores was then determined for each treatment group.…”

α-1-Adrenergic Receptor Agonist Activity of Clinical α-Adrenergic Receptor Agonists Interferes with α-2-Mediated Analgesia

“…They act by distinct mechanisms as evidenced by primarily spinal (NMDA) and peripheral (sulprostone) activity and their sensitivity to pharmacological antagonism. 12 In wildtype mice, intrathecal brimonidine, clonidine, and tizanidine significantly reduced sulprostone-and NMDA-induced allodynia to vehicle levels ( fig. 1A, table 1).…”

“…Male mice, weighing approximately 25 g, were administered 100 ng intrathecal N-methyl-D-aspartate (NMDA; Sigma Chemical Company, St. Louis, MO), 200 ng intrathecal or 300 ng/kg (in a 1 ml/kg volume) intraperitoneal sulprostone (Cayman Chemical Company, Ann Arbor, MI) to induce tactile hypersensitivity through different pain pathways as described in Gil et al 12 The alpha agonists brimonidine (UK 14,304 tartrate salt; Allergan, Inc.; 0.4 g), clonidine (Sigma; 0.4 g for the sulprostone model and 1 g for the NMDA model) and tizanidine (Sigma; 3 g) were coadministered intrathecally with the allodynic agent. In some experiments, various doses of ␣-2 agonists brimonidine, clonidine, and tizanidine were administered intraperitoneally 15 min before intrathecal NMDA or intraperitoneal sulprostone.…”