A critical time window for the analgesic effect of central histamine in the partial sciatic ligation model of neuropathic pain

Abstract

BackgroundIt is known that histamine participates in pain modulation. However, the effect of central histamine on neuropathic pain is not fully understood. Here, we report a critical time window for the analgesic effect of central histamine in the partial sciatic nerve ligation model of neuropathic pain.MethodsNeuropathic pain was induced by partial sciatic nerve ligation (PSL) in rats, wild-type (C57BL/6J) mice and HDC−/− (histidine decarboxylase gene knockout) and IL-1R−/− (interleukin-1 receptor gene knockout) mice. Histidine, a precursor of histamine that can increase the central histamine levels, was administered intraperitoneally (i.p.). Histidine decarboxylase (HDC) enzyme inhibitor α-fluoromethylhistidine was administered intracerebroventricularly (i.c.v.). Histamine H1 receptor antagonist mepyramine and H2 receptor antagonist cimetidine were given intrathecally (i.t.) and intracisternally (i.c.). Withdrawal thresholds to tactile and heat stimuli were measured with a set of von Frey hairs and infrared laser, respectively. Immunohistochemistry and Western blot were carried out to evaluate the morphology of microglia and IL-1β production, respectively.ResultsHistidine (100 mg/kg, i.p.) administered throughout days 0–3, 0–7, or 0–14 postoperatively (PO) alleviated mechanical allodynia and thermal hyperalgesia in the hindpaw following PSL in rats. Intrathecal histamine reversed PSL-induced thermal hyperalgesia in a dose-dependent manner and intracisternal histamine alleviated both mechanical allodynia and thermal hyperalgesia. Moreover, α-fluoromethylhistidine (i.c.v.) abrogated the analgesic effect of histidine. However, histidine treatment initiated later than the first postoperative day (treatment periods included days 2–3, 4–7, and 8–14 PO) did not show an analgesic effect. In addition, histidine treatment initiated immediately, but not 3 days after PSL, inhibited microglial activation and IL-1β upregulation in the lumbar spinal cord, in parallel with its effects on behavioral hypersensitivity. Moreover, the inhibitory effects on pain hypersensitivity and spinal microglial activation were absent in HDC−/− mice and IL-1R−/− mice. H1 receptor antagonist mepyramine (200 ng/rat i.t. or i.c.), but not H2 receptor antagonist cimetidine (200, 500 ng/rat i.t. or 500 ng/rat i.c.), blocked the effects of histidine on pain behavior and spinal microglia.ConclusionsThese results demonstrate that central histamine is analgesic within a critical time window in the PSL model of neuropathic pain via histamine H1 receptors. This effect may partly relate to the inhibition of microglial activation and IL-1β production in the spinal cord following nerve injury.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0637-0) contains supplementary material, which is available to authorized users.

Histaminergic transmission slows progression of amyotrophic lateral sclerosis

“…Enhancement of endogenous histaminergic transmission can be achieved in mice by either intracerebroventricular administration of histamine that has however only a limited translational value or by intraperitoneal administration of the histamine precursor histidine able to increase the histamine levels in the spinal cord, as we have confirmed here in SOD1‐G93A mice. We proved here that according to our pharmacological regimen, a sustained administration of histidine after symptoms insurgence ameliorated a wide range of molecular, neuropathological, and behavioural disease‐associated features.…”

“…In a different way, our recent studies exploring the actions of another histaminergic compound, clemastine, proved that also an anti‐histaminergic strategy reversing the inflammatory phenotype of microglia can exert positive outcomes in extending survival of ALS mice, but only when provided before the insurgence of symptoms . This may suggest that the therapeutic potential of central histamine in ALS mice shows a dual time window, as also demonstrated in a model of neuropathic pain . This is in line with the recognized dual role that histamine plays for instance in microglia, that is, detrimental under healthy conditions and beneficial within inflammatory environments .…”

“…Because histamine cannot penetrate the brain, we tested the efficacy of a histaminergic strategy in SOD1‐G93A mice, by using the histamine precursor histidine that is able to increase the central histamine levels by crossing the blood–brain barrier and being rapidly converted into histamine . Histidine (50–100–250 mg/kg) was injected in mice from the onset of clinical symptoms.…”

“…To overcome sex‐mixed results with low reproducibility, we used a single gender because of differences reported in male/female mice under pharmacological treatments. Female mice were randomly grouped into vehicle (0.9% NaCl) and histidine treatment groups at different doses (50, 100, and 250 mg/kg), based on previous results . Mice were injected i.p.…”

“…histidine treatment (100 mg/kg), spinal cords were isolated, homogenized with 3% perchloric solution, and centrifuged at 12 000 g , 4 °C for 20 min. Supernatants were collected and analysed for histamine content by HPLC, according to a previous study …”