Pleiotropic effect of histamine H4 receptor modulation in the central nervous system.

The histamine H4 receptor (H4R) is expressed primarily on cells involved in inflammation and immune responses. Recently, it has been reported the functional expression of H4R within neurons of the central nervous system, but their role has been poorly understood. The present study aimed to elucidate the physiopathological role of cerebral H4R in animal models by the intracerebroventricular administration of the H4R agonist VUF 8430 (20-40 µg per mouse). Selectivity of results was confirmed by the prevention of the effects produced by the H4R antagonist JNJ 10191584 (3-9 mg/kg p.o.). Neuronal H4R activation induced acute thermal antinociception, indicating that neuronal histamine H4R might be involved in the production of antinociception in the absence of an inflammatory process. An anxiolytic-like effect of intensity comparable to that exerted by diazepam, used as reference drug, was produced in the light-dark box test. VUF 8430 reversed the scopolamine-induced amnesia in the passive avoidance test and showed anorexant activity in food deprived mice. Conversely, the H4R activation did not modify the immobility time in the tail suspension test. Rotarod performance test was employed to demonstrate that the effects observed following the administration of VUF 8430 and JNJ 10191584 were not due to impaired motor function of animals. Furthermore, both compounds did not alter spontaneous mobility and exploratory activity in the hole board test. These results show the antinociceptive, antiamnesic, anxiolytic and anorexant effects induced by neuronal H4R agonism, suggesting that H4 modulators may have broader utility further the control of inflammatory and immune processes.

Effects of cannabinoid agonists on sheep sphincter of oddi in vitro.

BACKGROUND/AIMS: According to recent studies, the endocannabinoid system plays an important role in both physiological and pathophysiological situations. The purpose of the present study was to investigate the effects of cannabinoid (CB) agonists on isolated sheep sphincter of Oddi (SO)in vitro. METHODS: The isolated sheep SO tissues were mounted in organ baths and tested for isometric tension and cyclic GMP levels (cGMP) in response to the non-selective CB receptor agonist WIN 55,212-2 and the potent CB1 receptor agonist methanandamide in the presence and absence of the selective CB1 antagonist SR 141716A, the selective CB2 antagonist SR 144528 and the nonspecific inhibitor of nitric oxide (NO) synthase L-NAME. RESULTS: CB agonists relaxed SO in a concentration-dependent manner. These relaxations did not reduce in the presence of SR 144528 but were significantly reduced by SR 141716A and L-NAME. Carbachol significantly increased the cGMP levels compared with the control group and both of the CB receptor agonists significantly increased the cGMP levels compared with the control and carbachol groups. On the other hand, L-NAME prevented the increase in cGMP levels caused by CB agonists. CONCLUSION: These results show that the relaxation by the agonists may be through CB1 receptors. The decrease of CB relaxation responses by L-NAME, a nonspecific inhibitor of NO synthase, and the increase of cGMP levels in the SO tissues by CB agonists which decreased by L-NAME show that the relaxation effects of these agonists may also partially be via increasing the NO synthesis or release.

Low dose of donepezil improves gabapentin analgesia in the rat spared nerve injury model of neuropathic pain: single and multiple dosing studies.

The use of cholinergic drugs, either alone or in combination with other drugs, has been suggested as an approach to improve treatment outcome for patients suffering from neuropathic pain. The present study was undertaken in the rat spared nerve injury model of neuropathic pain to evaluate the effect of the cholinesterase inhibitor donepezil when administered (1) alone and (2) as low-dose in combination with the first-line recommendation gabapentin. The co-administration studies were performed following single and multiple dosing. Single, parenteral dosing of donepezil (1, 1.5 and 3 mg/kg s.c.) produced a dose-dependent reversal of the neuropathic pain behaviour. Co-administration of a sub-effective dose of donepezil (0.5 mg/kg s.c.) and low doses of gabapentin (10 and 30 mg/kg s.c.) resulted in a three- to fourfold increase of the analgesic effect, in comparison with gabapentin administered alone. Following multiple, oral dosing, gabapentin (25 mg/kg p.o.) was administered once daily over 20 days. Addition of donepezil (1.5 mg/kg p.o.) from day 11 to day 20 resulted in improved analgesia during the period of combination therapy, in comparison with the gabapentin monotherapy period. Furthermore, the treatment effects were stable in both the mono- and the combination therapy period, indicating that tolerance development does not occur within the studied time frame. In conclusion, the results from this preclinical study support the use of donepezil as adjunctive to gabapentin to improve the therapeutic outcome in the management of neuropathic pain.

Activation of opioid receptor like-1 receptor in the spinal cord produces sex-specific antinociception in the rat: estrogen attenuates antinociception in the female, whereas testosterone is required for the expression of antinociception in the male.

Sex-related differences in the perception and modulation of pain have been reported. The present study is the first to investigate systematically whether activation of opioid receptor-like 1 receptor (ORL1) by orphanin FQ (OFQ) produces sex-specific modulation of spinal nociception and whether estrogen or testosterone contributes to these differences using the rat as an experimental animal. Two behavioral models, the NMDA and heat-induced nociceptive tests, were used to examine sex-specific modulation of spinal nociception. Intrathecal microinjection of OFQ in male, ovariectomized (OVX), and diestrous rats produced a significant antinociceptive effect on both tests. However, OFQ failed to produce antinociception in proestrous rats, the phase of the estrous cycle with the highest levels of circulating estradiol, and produced a dose-dependent effect in OVX females treated with 1 ng to 100 microg of estradiol. The antinociceptive effects of OFQ were dose dependent in male and OVX animals and were reversibly antagonized by UFP-101 ([Nphe1,Arg14,Lys15]N/OFQ(1-13)-NH2), an ORL1 receptor-selective antagonist. Interestingly, OFQ was ineffective in gonadectomized (GDX) males, whereas testosterone replacement restored the antinociceptive effect of OFQ in GDX males. We conclude that OFQ produces sex-specific modulation of spinal nociception; estrogen attenuates antinociception in the female in parallel with normal cycling of estrogen levels, and testosterone is required for the expression of antinociception in the male; thus, the sensitivity of the male to the antinociceptive effects of OFQ is not simply attributable to the intrinsically low estrogen levels in these animals.

Microinjection of an adenosine A1 agonist into the medial pontine reticular formation increases tail flick latency to thermal stimulation.

BACKGROUND: Both pain and the pharmacologic management of pain can cause the undesirable effect of sleep disruption. One goal of basic and clinical neuroscience is to facilitate rational drug development by identifying the brain regions and neurochemical modulators of sleep and pain. Adenosine is thought to be an endogenous sleep promoting substance and adenosinergic compounds can contribute to pain management. In the pontine brain stem adenosine promotes sleep but the effects of pontine adenosine on pain have not been studied. This study tested the hypothesis that an adenosine agonist would cause antinociception when microinjected into pontine reticular formation regions that regulate sleep. METHODS: The tail flick latency (TFL) test quantified the time in seconds for an animal to move its tail away from a thermal stimulus created by a beam of light. TFL measures were used to evaluate the antinociceptive effects of the adenosine A1 receptor agonist N6-p-sulfophenyladenosine (SPA). Pontine microinjection of SPA (0.1 microg/0.25 microl, 0.88 mm) was followed by TFL measures as a function of time after drug delivery and across the sleep-wake cycle. RESULTS: Compared with saline (control), pontine administration of the adenosine agonist significantly increased latency to tail withdrawal (P < 0.0001). The increase in antinociceptive behavior evoked by the adenosine agonist SPA was blocked by pretreatment with the adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX, 0.75 ng/0.25 microl, 10 microm). CONCLUSIONS: These preclinical data encourage additional research on the cellular mechanisms by which adenosine in the pontine reticular formation contributes to the supraspinal modulation of pain.

Spinal administration of selective opioid antagonists in amphibians: evidence for an opioid unireceptor.

In mammals, opioids act by interactions with three distinct types of receptors: mu, delta, or kappa opioid receptors. Using a novel assay of antinociception in the Northern grass frog, Rana pipiens, previous work demonstrated that selective mu, delta, or kappa opioids produced a potent antinociception when administered by the spinal route. The relative potency of this effect was highly correlated to that found in mammals. Present studies employing selective opioid antagonists, beta-FNA, NTI, or nor-BNI demonstrated that, in general, these antagonists were not selective in the amphibian model. These data have implications for the functional evolution of opioid receptors in vertebrates and suggest that the tested mu, delta, and kappa opioids mediate antinociception via a single type of opioid receptor in amphibians, termed the unireceptor.