Histamine modulation of acute nociception involves regulation of Nav 1.8 in primary afferent neurons in mice.

AIMS: To explore the role of histamine in acute pain perception and its possible mechanisms. METHODS: Pain-like behaviors induced by four types of noxious stimuli (hot-plate, tail-pressure, acetic acid, and formalin) were accessed in mice. Nav 1.8 expression and functions in primary afferent neurons were compared between histidine decarboxylase knockout (HDC(-/-) ) mice and their wild-types. RESULTS: HDC(-/-) mice, lacking in endogenous histamine, showed elevated sensitivity to all these noxious stimuli, as compared with the wild-types. In addition, a depletion of endogenous histamine with α-fluoromethylhistidine (α-FMH), a specific HDC inhibitor, or feeding mice a low-histamine diet also enhanced nociception in the wild-types. Nav 1.8 expression in primary afferent neurons was increased both in HDC(-/-) and in α-FMH-treated wild-type mice. A higher Nav 1.8 current density, a lower action potential (AP) threshold, and a higher firing rate in response to suprathreshold stimulation were observed in nociception-related small DRG neurons of HDC(-/-) mice. Nav 1.8 inhibitor A-803467, but not TTX, diminished the hyperexcitability and blocked repetitive AP firing of these neurons. CONCLUSION: Our results indicate that histamine participates in acute pain modulation in a dose-related manner. The regulation of Nav 1.8 expression and the excitability of nociceptive primary afferent neurons may be involved in the underlying mechanisms.

Effects of histamine on spontaneous neuropathic pain induced by peripheral axotomy.

The present study was designed to investigate the effects of histamine on spontaneous neuropathic pain (NP) induced by peripheral axotomy. Rats and mice were subjected to complete transection of the left sciatic and saphenous nerves to induce spontaneous NP (the neuroma model). Rats were then treated with drugs once daily for 30 days (histidine and loratadine, i.p.) or 21 days (histamine, i.c.v.). Autotomy behavior was scored daily until day 50 post-operation (PO). On days 14 to 21 PO, some rats in the control group were subjected to single-fiber recording. Autotomy behavior was also monitored daily in histidine decarboxylase (the key enzyme for histamine synthesis) knockout (HDC(-/-)) and wild-type mice for 42 days. We found that both histidine (500 mg/kg) (a precursor of histamine that increases histamine levels in the tissues) and histamine (50 µg/5 µL) significantly suppressed autotomy behavior in rats. HDC(-/-) mice lacking endogenous histamine showed higher levels of autotomy than the wild-type. In addition, the analgesic effect of histidine was not antagonized by loratadine (a peripherally-acting H1 receptor antagonist), while loratadine alone significantly suppressed autotomy. Electrophysiological recording showed that ectopic spontaneous discharges from the neuroma were blocked by systemic diphenhydramine (an H1 receptor antagonist). Our results suggest that histamine plays an important role in spontaneous NP. It is likely that histamine in the central nervous system is analgesic, while in the periphery, via H1 receptors, it is algesic. This study justifies the avoidance of a histamine-rich diet and the use of peripherally-acting H1 receptor antagonists as well as agents that improve histamine action in the central nervous system in patients with spontaneous NP.

[Role of voltage-sodium channels in neuropathic pain].

Voltage-gated sodium channels are critical for the generation and conduction of nerve impulses. Recent studies show that in primary sensory neurons, the expression and dynamic regulation of several sodium channel subtypes play important roles in neuropathic pain. A number of SCN9A (encoding Nav1.7) gene point mutations are related with human genetic pain disorders. Transgenic and specific knockout techniques have revealed that Nav1.3, Nav1.8, Nav1.9 are important for the development and maintenance of neuropathic pain condition. Specific blockers of these sodium channels have been demonstrated to be effective in alleviating allodynia and hyperalgesia. Here we reviewed the roles of sodium channels in neuropathic pain, which may be applicable for the development of new drugs with enhanced efficacy for neuropathic pain treatment.

Ameliorating effect of histamine on impairment of cued fear extinction induced by morphine withdrawal in histidine decarboxylase gene knockout mice.

AIM: Histamine plays an important role in morphine addiction and memory-dependent behavior. However, little is known about the effect of histamine on the impairment of memory after morphine withdrawal. This study was designed to investigate the effect of histamine on memory impairment induced by morphine withdrawal in histidine decarboxylase knockout (HDC-KO) and wild-type (WT) mice. METHODS: WT and HDC-KO mice were given subcutaneous morphine or saline twice daily for 5 consecutive days. The mice received a cued or contextual fear conditioning session 7 days after the last injection. During subsequent days, mice received 4 cued or contextual extinction sessions (one session per day). Western blot was used to assess extracellular signal-regulated kinase (ERK) phosphorylation in the amygdala and hippocampus. RESULTS: Morphine withdrawal did not affect the acquisition of cued or contextual fear responses. It impaired cued but not contextual fear extinction. The acquisition of cued and contextual fear responses was accelerated in HDC-KO mice. Histamine deficiency aggravated the impairment of cued fear extinction induced by morphine withdrawal, whereas histamine (icv, 5 µg/mouse) reversed this effect. Morphine withdrawal decreased ERK phosphorylation in the amygdala after cued fear extinction, especially in HDC-KO mice. CONCLUSION: These results suggest that morphine withdrawal specifically impairs cued fear extinction and histamine ameliorates this impairment. Its action might be mediated by the modulation of ERK phosphorylation in the amygdala. Histamine should be explored for possible roles in the prevention or treatment of morphine abuse and relapse.

Morphine induces conditioned place preference behavior in histidine decarboxylase knockout mice.

Pharmacological and lesion studies have shown that histamine exerts inhibitory effects on morphine-induced reward-seeking behavior. The present study was designed to further investigate the involvement of endogenous histamine in morphine-induced reward-seeking behavior using histidine decarboxylase gene knockout (HDC-KO) mice. Conditioned place preference (CPP) was present in both wild-type (WT) and HDC-KO mice treated with 5 or 10 mg/kg morphine. HDC-KO mice showed stronger morphine-induced CPP as compared with WT mice. Meanwhile, morphine significantly increased dopamine level in the VTA and NAc, especially in HDC-KO mice. However, the extinction of CPP is similar between WT and HDC-KO mice. Moreover, naloxone-precipitated withdrawal jumping was markedly decreased in HDC-KO mice. These results indicate that endogenous histamine inhibits the development, but not the extinction, of morphine-induced CPP and reduces morphine withdrawal sign, probably through modulating dopaminergic activity in the brain.