Efficacy of improgan, a non-opioid analgesic, in neuropathic pain

Abstract

Improgan, a non-opioid analgesic, is known to act in the rodent brain stem to produce highly effective antinociception in several acute pain tests. However, improgan has not been studied in any models of chronic pain. To assess the efficacy of improgan in an animal model of neuropathic pain, the effects of this drug were studied on mechanical allodynia following unilateral spinal nerve ligation (SNL) in rats. Intracerebroventricular (icv) improgan (40 – 80 µg) produced complete, reversible, dose-dependent attenuation of hind paw mechanical allodynia for up to one hr after administration, with no noticeable behavioral or motor side effects. Intracerebral (ic) microinjections of improgan (5 – 30 µg) into the rostral ventromedial medulla (RVM) also reversed the allodynia, showing this brain area to be an important site for improgan’s action. The recently-demonstrated suppression of RVM ON-cell activity by improgan may account for the presently-observed anti-allodynic activity. The present findings suggest that brain-penetrating, improgan-like drugs developed for human use could be effective medications for the treatment of neuropathic pain.

Antinociceptive activity of CC44, a biotinylated improgan congener

“…The present results show that CC44 is 5 to 8.5-fold more potent than improgan on the rat tail flick test (Hough et al, 2006), the mouse tail immersion test (Hough et al, 2002), and on rat anti-allodynic activity (Albrecht et al, 2011). Similarly, intra-RVM injections of the two drugs in rats found that 30 nmol of CC44 gave responses equivalent to 145 nmol of improgan (Nalwalk et al, 2004), a 4.8 fold difference.…”

“…Although activation of OFF-cells is thought to mediate acute analgesic properties, improgan (i.c.v.) also suppresses the firing of pain-enhancing RVM ON-cells, which may account for the attenuation of neuropathic allodynia by this drug (Heinricher et al, 2010; Albrecht et al, 2011). …”

“…I.c.v. improgan also suppresses the firing of pain-enhancing RVM ON-cells (Heinricher et al, 2010), an effect suggested to account for the attenuation of SNL allodynia by this drug (Albrecht et al, 2011). CC44’s activity in the same model suggests a similar mechanism, but electrophysiological studies are needed to validate this hypothesis.…”

“…1), an imidazole-containing analgesic drug derived from the H 2 receptor antagonist cimetidine, is one such drug (Li et al, 1996; Hough et al, 2001a). When administered directly into the CNS, improgan is highly effective in thermal (Li et al, 1996), mechanical (Li et al, 1997) and neuropathic pain tests (Albrecht et al, 2011). Like morphine (Basbaum and Fields, 1984), improgan acts in the periaqueductal gray and rostral ventromedial medulla (RVM) to stimulate descending analgesic pathways (Nalwalk et al, 2004; Phillips et al, 2012).…”

Pharmacological Management of Neuropathic Pain: Current Trends and Possible Approaches

“…Rostral ventral medulla on-cell modulators (improgan) are effective against mechanical allodynia following unilateral spinal nerve ligation in rats (116). Further, inhibiting brain P450 epoxygenase activity abolishes the improgan antinociception; thus providing a future hope for newer non-opioid, non-cannabinoid analgesics acting through supra-spinal sites to inhibit NP.…”