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.
Highlights
It is known that histamine participates in pain modulation
Inhibition of Histidine decarboxylase (HDC) enzyme or knockout of HDC gene abolished the effects of histidine on pain behavior and microglial activation Since histidine cannot be transformed to histamine without HDC enzyme, we introduced the inhibitor of HDC α-FMH and HDC gene knockout mice (HDC−/−) to further verify the effects of histidine are attributed to histamine
Based on the knowledge that systemic histidine increases the cerebral levels of histamine [8, 9], together with the following evidence obtained from the present study, (1) systemic administration of histidine increased histamine levels in the medulla and lumbar spinal cord; (2) intrathecal and intracisternal injection of histamine prevented the development of neuropathic pain; (3) and inhibition of HDC enzyme or HDC gene knockout, both of which interrupt the synthesis of histamine from histidine, abolished the analgesic effect of histidine; and (4) both intrathecal and intracisternal injection of H1 receptor antagonist mepyramine antagonized the analgesic effect of histidine, we conclude that the analgesic effect of histidine is largely attributed to central histamine
Summary
It is known that histamine participates in pain modulation. the effect of central histamine on neuropathic pain is not fully understood. As for neuropathic pain, Huang et al found that, 2 weeks after nerve injury, a low dose of histamine given intracerebroventricularly (i.c.v.) decreases while a high dose of histamine increases the nociceptive threshold to mechanical stimulation [14]. These findings reflect the acute or transient effect of central histamine on pain sensation in the context of neuropathic pain, but its effect on the development of neuropathic pain remains unclear. We hypothesize that central histamine might be a member among a variety of factors [16, 17] that are involved in pathophysiological processes in the CNS following nerve injury and contribute to the development of neuropathic pain in CRPS-2
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