GW274150, a novel and highly selective inhibitor of the inducible isoform of nitric oxide synthase (iNOS), shows analgesic effects in rat models of inflammatory and neuropathic pain

Abstract

Nitric oxide (NO), synthesised by different isoforms of nitric oxide synthase (NOS), has been linked with the development and maintenance of nociception. We studied the role of the inducible isoform, iNOS, in two different rat pain models with an inflammatory component. iNOS was immunohistochemically detected locally in the paw 6h after Freund's Complete Adjuvant (FCA) injection, showing a plateau at 24-72 h and falling slowly in the following weeks. This correlated with the late phase of the hypersensitivity to pain revealed in the behavioural tests. A highly selective iNOS inhibitor GW274150 (1-30 mg/kg orally, 24h after FCA) suppressed the accumulation of nitrite in the inflamed paw indicating substantial iNOS inhibition. At the same time it partially reversed FCA-induced hypersensitivity to pain and edema in a dose-dependent manner. After Chronic Constriction Injury (CCI) surgery to the sciatic nerve, iNOS presence was only detected locally in the region of the nerve (inflammatory cells). GW274150 (3-30 mg/kg orally, 21 days after surgery) also reversed significantly the CCI-associated hypersensitivity to pain. No iNOS was detectable in dorsal root ganglia, spinal cord or brain in either model. This study demonstrates a role for peripherally-expressed iNOS in pain conditions with an inflammatory component and the potential value of iNOS inhibitors in such conditions.

Pharmacological Characterization of KLYP961, a Dual Inhibitor of Inducible and Neuronal Nitric-Oxide Synthases

“…Although many initial substrate mimetics had dose-limiting cardiovascular signals, such as increased blood pressure via inhibition of eNOS, substrate-competitive, time-dependent iNOS inhibitors such as GW274150 with optimum selectivity against eNOS have been identified. The preclinical profile supports a role for NO derived from iNOS in both inflammatory pain and neuropathic pain states (De Alba et al, 2006). In addition to serving as a substrate for NOS isoforms, arginine participates in a physiologically important amino acid metabolic cycle.…”

“…Of particular relevance to pain and inflamma-1 tion, 1) NO is involved in the transmission and modulation of nociceptive information at peripheral, spinal, and supraspinal levels (Yamamoto et al, 1993;Goettl and Larson, 1996;Wu et al, 2001), 2) NO contributes to the development and maintenance of central sensitization (Haley et al, 1992;Malmberg and Yaksh, 1993;Meller and Gebhart, 1993;Wu et al, 2001) and peripheral neuropathic pain (Levy and Zochodne, 1998;Levy et al, 1999), 3) NO is a pronociceptive mediator that synergizes with hyperalgesic prostaglandins in nociceptor sensitization (Aley et al, 1998), and importantly, 4) NO-donating compounds induce hyperalgesia and migraine in humans and hyperalgesia in nonhuman primates and rodents (Holthusen and Arndt, 1994;Kawabata et al, 1994;Aley et al, 1998;Lin et al, 1999). Antinociceptive activity of structurally diverse iNOS-selective inhibitors, as well as nonselective NOS inhibitors (Tao et al, 2003;De Alba et al, 2006;LaBuda et al, 2006;Tang et al, 2007), provides further rationale for the pursuit of NOS inhibitors as therapeutics for pain and inflammation. Currently, one iNOS active-site inhibitor, GW274150, ([2-[(1-iminoethyl) amino]ethyl]-L-homocysteine) is in clinical trials.…”

The antinociceptive effects of magnesium sulfate and MK-801 in visceral inflammatory pain model: The role of NO/cGMP/K+ATP pathway

“…These contradictions might be explained by considering that NO is a controversial molecule with dual effects, depending on its concentrations, NOS isoforms, redox balance, and the function of neuron subpopulations (Kawabata, 1994;Zhang et al, 2006). On one hand, increased NO production has been shown to produce antinociception (Bulutcu et al, 2002;Galdino et al, 2010;Garrido-Suárez et al, 2009;Granados-Soto et al, 1997;Sachs et al, 2004), on the other hand, NOS inhibitors elicit antinociception in some models of acute and persistent pain (De Alba et al, 2006;Milovanović et al, 2009;Yonehara et al, 1997).…”

The Role of Nitric Oxide in the Local Antiallodynic and Antihyperalgesic Effects and Expression of δ-Opioid and Cannabinoid-2 Receptors during Neuropathic Pain in Mice

“…Accordingly, the expression of NOS1 and NOS2 is up-regulated in the spinal cord and dorsal root ganglia after nerve injury (Levy et al, 1999;De Alba et al, 2006). Moreover, the systemic administration of selective NOS or guanylate cyclase inhibitors might reverse the hypersensitivity to pain induced by the spinal or sciatic nerve injury (De Alba et al, 2006;LaBuda et al, 2006;Guan et al, 2007), but the involvement of the peripheral nitric oxide-cGMP-PKG pathway in the maintenance of thermal and mechanical hypersensitivity induced by the chronic constriction of the sciatic nerve is not completely established.…”