Effects of S 38093, an antagonist/inverse agonist of histamine H3 receptors, in models of neuropathic pain in rats

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Histamine H3 receptors are mainly expressed on <jats:styled-content style="fixed-case">CNS</jats:styled-content> neurons, particularly along the nociceptive pathways. The potential involvement of these receptors in pain processing has been suggested using H3 receptor inverse agonists.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>The antinociceptive effect of S 38093, a novel inverse agonist of H3 receptors, has been evaluated in several neuropathic pain models in rat and compared with those of gabapentin and pregabalin.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>While S 38093 did not change vocalization thresholds to paw pressure in healthy rats, it exhibited a significant antihyperalgesic effect in the Streptozocin‐induced diabetic (<jats:styled-content style="fixed-case">STZ</jats:styled-content>) neuropathy model after acute and chronic administration and, in the chronic constriction injury (<jats:styled-content style="fixed-case">CCI</jats:styled-content>) model only after chronic administration, submitted to the paw‐pressure test. Acute S 38093 administration at all doses tested displayed a significant cold antiallodynic effect in a model of acute or repeated administration of oxaliplatin‐induced neuropathy submitted to cold tail immersion, cold allodynia being the main side effect of oxaliplatin in patients. The effect of S 38093 increased following chronic administration (i.e. twice a day during 5 days) in the <jats:styled-content style="fixed-case">CCI</jats:styled-content> and <jats:styled-content style="fixed-case">STZ</jats:styled-content> models except in the oxaliplatin models where its effect was already maximal from the first administration The kinetics and size of effect of S 38093 were similar to gabapentin and/or pregabalin. Finally, the antinociceptive effect of S 38093 could be partially mediated by α2 adrenoreceptors desensitization in the locus coeruleus.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>These results highlight the interest of S 38093 to relieve neuropathic pain and warrant clinical trials especially in chemotherapeutic agent‐induced neuropathic pain.</jats:p></jats:sec><jats:sec><jats:title>Significance</jats:title><jats:p>S 38093, a new H3 antagonist/inverse agonist, displays antiallodynic and antihyperalgesic effect in neuropathic pain, especially in oxaliplatin‐induced neuropathy after chronic administration. This effect of S 38093 in neuropathic pain could be partly mediated by α2 receptors desensitization in the locus coeruleus.</jats:p></jats:sec>