Is the Second Phase of the Formalin Test Useful to Predict Activity in Chronic Constriction Injury Models? A Pharmacological Comparison in Different Species

Abstract

This study presents data of several reference drugs in rats and gerbils for both the second phase of the formalin test and the cold allodynia in animals with a constriction injury of the sciatic nerve. A pharmacological validation of the formalin test and the CCI model in gerbils was performed. It was evaluated whether the second phase of the formalin test could be used as a pharmacological screening to predict outcome in the cold plate test in CCI animals. Male Sprague Dawley and Wistar rats and male gerbils were used for both tests. For the formalin test, animals were injected in the right hind paw (5% formalin rat: 0.05 microl; gerbil: 0.01 microl) and flinching and licking or biting were recorded. For CCI testing, a Bennett operation was performed on the left hind paw 7 days before testing. Cold plate allodynia was evaluated before and after drug treatment. In rats, a good correlation between both test conditions for morphine, fentanyl, MK-801 and flunarizine was found. Clonidine tends to have more activity in the second phase of the formalin test, whereas baclofen, tramadol, amitryptiline, ketamine and topiramate demonstrate to be more active in the cold plate. In gerbils, a good correlation between both test conditions for fentanyl and ketoprofen was found. Tramadol and CP-96345 tend to have more activity in the second phase of the formalin test, whereas morphine, SR-48968, SR-142801 and R116301 demonstrates to be more active in the cold plate test. In the present acute test conditions, there is a correlation in the pharmacological activity in rats and gerbils for the tested compounds a correlation between the second phase of the formalin test and the cold allodynia in CCI animals is found. Comparing to human data the screening drugs tested in this study show a correlation between animal and human studies in these specific circumstances. Further validation studies are needed to make these correlations clinical applicable.

The role of alpha5 nicotinic acetylcholine receptors in mouse models of chronic inflammatory and neuropathic pain

“…Thermal nociception and early phase response (phase I) in the formalin test are caused predominantly by direct activation of peripheral C-fibers, whereas the late response (phase II) in the formalin test involves functional changes in the dorsal horn of the spinal cord (i.e., central sensitization) [30,31]. In this study, α 5 KO and WT mice were tested in the formalin test at 2.5 % concentrations.…”

“…Our current data demonstrate that, in both chronic inflammatory and neuropathic pain models, nicotine blocks mechanical allodynia in a α 5 *-dependent manner. It is therefore possible that the modest efficacy of some α 4 β 2 * agonists reported in animal models of chronic inflammatory pain [31] and initial clinical studies [44–46]; may be related to their insufficient binding and/or functional activity at α 5 * subtypes. We believe that the refocusing of nicotinic analgesic development on α 5 *-containing receptors will lead to more efficacious compounds.…”

Assessment of 5-HT7Receptor Agonists Selectivity Using Nociceptive and Thermoregulation Tests in Knockout versus Wild-Type Mice

“…Thermal nociception and early phase response in the formalin test are caused predominantly by direct activation of peripheral C-fibers, whereas the late response (phase II) in the formalin test involves functional changes in the dorsal horn of the spinal cord (i.e., central sensitization) [41–43]. In this study, subcutaneous administration of 5-HT 7 receptor agonists was devoid of activity in acute nociceptive tests (i.e., thermal- and formalin-induced phase I nociception), but exerted clear-cut antinociceptive effects in phase II of the formalin test in wild-type mice.…”

Antinociceptive effect of an ethanolic extract of the aerial parts of Hilleria latifolia (Lam.) H. Walt. (Phytolaccaceae)

“…It is undoubtedly the most predictive of acute pain[9] and very popular for the rapid and easy screening of pharmacological targets in drug evaluation. [3233] HLE showed significant antinociceptive effects in this model. The formalin test produces a distinct biphasic nociceptive response.…”