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Analgesic Efficacy of CR4056, a Novel imidazoline-2 Receptor Ligand, in Rat Models of Inflammatory and Neuropathic Pain

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Analgesic Efficacy of CR4056, a Novel imidazoline-2 Receptor Ligand, in Rat Models of Inflammatory and Neuropathic Pain

Flora Ferrari et al. J Pain Res.

Abstract

Two decades of investigations have failed to unequivocally clarify the functions and the molecular nature of imidazoline-2 receptors (I2R). However, there is robust pharmacological evidence for the functional modulation of monoamino oxidase (MAO) and other important enzyme activities by I2 site ligands. Some compounds of this class proved to be active experimental tools in preventing both experimental pain and opioid tolerance and dependence. Unfortunately, even though these compounds bind with high potency to central I2 sites, they fail to represent a valid clinical opportunity due to their pharmacokinetic, selectivity or side-effects profile. This paper presents the preclinical profile of a novel I2 ligand (2-phenyl-6-(1H-imidazol-1yl) quinazoline; [CR4056]) that selectively inhibits the activity of human recombinant MAO-A in a concentration-dependent manner. A sub-chronic four day oral treatment of CR4056 increased norepinephrine (NE) tissue levels both in the rat cerebral cortex (63.1% ±4.2%; P < 0.05) and lumbar spinal cord (51.3% ± 6.7%; P < 0.05). In the complete Freund's adjuvant (CFA) rat model of inflammatory pain, CR4056 was found to be orally active (ED50 = 5.8 mg/kg, by mouth [p.o.]). In the acute capsaicin model, CR4056 completely blocked mechanical hyperalgesia in the injured hind paw (ED50 = 4.1 mg/kg, p.o.; ED100 = 17.9 mg/kg, p.o.). This effect was dose-dependently antagonized by the non-selective imidazoline I2/α2 antagonist idazoxan. In rat models of neuropathic pain, oral administration of CR4056 significantly attenuated mechanical hyperalgesia and allodynia. In summary, the present study suggests a novel pharmacological opportunity for inflammatory and/or neuropathic pain treatment based on selective interaction with central imidazoline-2 receptors.

Keywords: CR4056; allodynia; hyperalgesia; imidazoline-2 receptors; inflammatory pain; neuropathic pain.

Figures

Figure 1
Figure 1
Effects of acute and sub-chronic oral treatment (once daily for 4 days) with CR4056 on endogenous norepinephrine (NE) levels in rat parieto-occipital cortex, lumbar spinal cord (L4–L6) and plasma. Notes: Data represent the mean NE levels expressed as pg/sample ± SEM (n = 5). *P < 0.05 versus basal NE levels found in rats administered with vehicle (Student’s t-test).
Figure 2
Figure 2
Antinociceptive effects of CR4056 on CFA-induced inflammatory pain in rats (Randall-Selitto test). CR4056 was orally administered 24 hours after a CFA injection in the right hind paw of the rats. Piroxicam (10 mg/kg; oral) was used as a positive control. Notes: Data represent the mean withdrawal threshold expressed in grams ± SEM (n = 6 per group).
Figure 3
Figure 3
Capsaicin-induced neurogenic/inflammatory pain in rats: effect of increasing oral doses of CR4056 (Randall–Selitto test). CR4056 (range: 3–30 mg/kg) dose-dependently reversed the mechanical hyperalgesia induced by an intraplantar injection of capsaicin (F[5, 36] = 27.57, P < 0.001). Piroxicam (10 mg/kg; oral) was used as a positive control. Notes: Data represent the mean withdrawal threshold expressed in grams ± SEM (n = 6 per group).
Figure 4
Figure 4
Capsaicin-induced neurogenic/inflammatory pain in rats (Randall–Selitto test). Panel A: effects of different receptor antagonists on the analgesic activity induced by 30 mg/kg oral CR4056. Notes: Data represent the mean percent area under the curve (AUC) ± SEM in the absence or presence of the antagonist (n = 6 per group). *P < 0.05 versus CR4056 treated animals (Holm–Sidak test). Panel B: dose-dependent effect of idazoxan on the analgesic activity induced by 30 mg/kg oral CR4056. Data represent the mean withdrawal threshold expressed in grams ± SEM (n = 6 per group).
Figure 5
Figure 5
Isobologram for the effects of CR4056 and morphine, alone or in combination, in capsaicin-induced neurogenic/inflammatory pain in rats. Filled circle corresponds to the experimental co-treatment ED50 with 95% confidence limits; open square corresponds to the experimental ED50 for morphine alone, and open diamond corresponds to the experimental ED50 for CR4056 alone.
Figure 6
Figure 6
Streptozotocin (STZ)-induced neuropathic (diabetic, type I) pain in rats: effects of increasing oral doses of CR4056 (Randall–Selitto test). Diabetes was induced in rats by administration of a single dose of STZ (i.p.). CR4056 was orally administered four weeks after the STZ injection. Morphine (20 mg/kg; s.c.), was used as a positive control. Note: Data represent the mean withdrawal threshold expressed in grams ± SEM (n = 7 per group).
Figure 7
Figure 7
Antiallodynic effects of CR4056 in the acid-induced muscle allodynia model in rats (Dynamic Plantar Aesthesiometer; Ugo Basile, VA, Italy). Right gastrocnemius muscle was injected with acidic saline (pH = 4). Five days later (d5), the same gastrocnemius muscle was re-injected using an identical injection protocol. As a control for the injection procedure, a separate group of animals were injected with sterile saline. Six days after the first acidic saline injection, CR4056 was orally administered to rats two hours before testing. Gabapentin (GBP) (30 mg/kg; i.p.) was used as positive control. Notes: Data represent the mean withdrawal threshold expressed in grams (n = 6 per group). Standard errors of the mean (SEM) have been omitted for clarity of presentation (available as supplementary data in Table S4). Abbreviations: DX, right paw; SX, left paw.

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