Modulatory Role Of Central Histamine In Neuropathic Pain Of Complex Regional Pain Svndrome-Ⅱ

PART ⅠCentral histamine is analgesic through early inhibition of spinal microglial activation in a rodent model of CRPS-ⅡIt is known that histamine participates in pain modulation. However, its effect on neuropathic pain is not fully understood. Here we investigated the effect of central histamine and H3 receptor antagonists on pain hypersensitivity in a rodent model of complex regional pain syndrome-2 (CRPS-2) induced by partial sciatic nerve ligation (PSL). Histidine, the precursor of histamine, was intraperitoneally injected once daily to increase the contents of central histamine. It was found that histidine (100 mg/kg) administered throughout postoperative days 0-3,0-7 or 0-14 alleviated mechanical allodynia and thermal hyperalgesia in the hindpaw following PSL in rats. However, histidine treatment starting from later than the first day (treatment periods included postoperative days 2-3,4-7 and 8-14) did not have analgesic effect. Moreover, 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. In addition, the analgesic effect of histamine was abolished by intrathecal injection of 10 ng IL-1β, and both the analgesic effect and the inhibitory effect on spinal microglial activation were absent in IL-1R"’" mice. Knockout of histidine decarboxylase (HDC) gene in mice or inhibition of HDC enzyme activity by a-fluoromethylhistidine (i.c.v.) in rats abolished the analgesic effect of histidine. Moreover, histamine (100 and 200 ng/rat, i.t.) completely reversed thermal hyperalgesia following PSL and the inhibitory effect on spinal microglial activation was absent in HDC-/- mice. H1 receptor antagonist mepyramine (200 ng/rat i.t.), but not H2 receptor antagonist cimetidine (200,500 ng/rat i.t.), blocked the analgesic effect of histidine and its inhibitory effect on spinal microglial activation. Our results indicate that central histamine is analgesic during the early phase of neuropathic pain development in PSL model of CRPS-2 by suppressing IL-1β production in spinal microglia through histamine H1 receptors. Therefore, intervention approaches such as increasing levels of central histamine should be initiated as early as possible after nerve injury.PART ⅡHistamine H3 receptor antagonists augment excitatory synaptic transmission in locus coeruleus:possible mechanism for the analgesic effect of thioperamide on CRPS-ⅡThe results in Part I had demonstrated that the increase in central histamine levels by systemical histidine administration had an analgesic effect in neuropathic pain of CRPS-2 induced by PSL. However, exogenous histamine cannot cross the blood brain barrier and the central application is invasive and clinically limited. On the other hand, activation of peripheral histamine H1, H2 receptor by exogenous histamine often induces side effects, such as peripheral inflammation or excessive gastric acid secretion. Moreover, the results in Part I also indicate that the analgesic effect of histidine is early phase dependent. All the above-mentioned factors seriously hinder the clinical application of histamine. As a result, histamine H3 receptor antagonists, which can modulate the synthesis and release of histamine, have been a new and popular research target recently.In this experiment, we found that administration of thioperamide (H3 receptor antagonist) (15 μg,30 μg/mice, i.c.v.) once daily for 7 days significantly depressed bilateral allodynia and ipsilateral hyperalgesia induced by PSL in a dose-dependent manner. Thioperamide (30 μg/mice, i.c.v.) also depressed the contralateral hyperalgesia. The analgesic effect of thioperamide was reversed by immepip (a selective agonist of H3 receptor). Another H3 receptor antagonist clobenpropit (30 μg/mice, i.c.v.) also had a bilateral analgesic effect in PSL mice. Moreover, administration of thioperamide during 7-14 days PO (30 μg/mice, i.c.v.) or in one bolus on day 7 PO showed an analgesic effect. Moreover, H3R gene knockout (H3R-/-) blocked the development of neuropathic pain in PSL mice and thioperamide had no further effect in H3R-/- mice. However, to our surprise, H1 and H2 receptor antagonists or a-FMH could not block the analgesic effect of thioperamide, while thioperamide depressed the hypersensitivity of HDC-/- mice induced by PSL. It was reported that administration of a-1 receptor antagonist could reverse the effect of thioperamide, indicating the relationship between LC-norepinephrine system and the function of H3 receptor antagonists. So we observed the changes of electrophysiology of LC neurons and found that the firing frequency of spontaneous action potential (sAP) was decreased after PSL, and thioperamide had no effect on this decrease. However, thioperamide (10 μM) significantly increased the frequency of spontaneous EPSC of LC neurons both before and after the PSL. These results suggest that thioperamide has an analgesic effect on CRPS-2 induced by PSL, which is histamine independent but through enhancement of excitatory synaptic transmission strength in LC neurons.