Neuroprotective Effects of Drug-Induced Therapeutic Hypothermia in Central Nervous System Diseases.

OBJECTIVE: This review article focuses on the neuroprotective effect of drug-induced hypothermia in cerebrovascular diseases and discusses its related side effects. METHOD: A systematic literature search was performed using Pubmed and Embase electronic databases for a retrospective analysis. RESULTS: Experimental studies have shown that drug-induced hypothermia alleviates brain damage and plays a neuroprotective role, thereby reducing mortality and ameliorating neurological deficits. Therefore, drug-induced hypothermia has an important research value and is worth further consideration in the clinical setting. However, drug-induced hypothermia is also associated with side effects, such as ventricular tachycardia, ventricular fibrillation, suppressed immune function, infection, electrolyte imbalance, glucose metabolism disorders, and skeletal muscle tremor. Existing drugs with cooling effects belong to the following categories: (1) dopamine receptor agonists; (2) cannabis; (3) opioid receptors; (4) vanilloid receptors; (5) vasopressins (potent neurotensin receptor agonists); (6) thyroid drugs; (7) adenosine drugs; and (8) purine drugs.

Avaliação da analgesia controlada pelo paciente no pós-operató-rio de cirurgia cardíaca, com infusão continua de morfina / Evaluation of patient-controlled analgesia in the postoperative period of heart surgery with morphine continuous infusion

Justificativa e objetivos: A bomba de analgesia controlada pelo paciente (ACP) permite que sejam administrados opioides de forma segura e em diferentes programações. O objetivo deste estudo foi avaliar a analgesia, efeitos colaterais e o consumo analgésico de pacientes em pós operatório de cirurgia cardíaca que utilizaram ACP na programação contínua mais bolus com morfina, por via venosa. Método: Estudo prospectivo unicêntrico. O acompanhamento foi realizado a partir da extubação dos pacientes a cada 6h,até 30h. Foram analisadas as seguintes variáveis: intensidade de dor, o consumo de analgésico, número de solicitações de analgésicos e ocorrência de efeitos colaterais.Resultados: A ausência da dor foi verificada em 86 por cento dospacientes, os efeitos colaterais predominantes foram náuseas e vômitos, houve diminuição significante no consumo e nasolicitação de morfina. Conclusão: A programação contínua mais bolus foi segura e eficaz no controle da dor.

Background and objectives: Patient-controlled analgesia pump (PCA) allows for the safe administration of opioids in different schedules. This study aimed at evaluating analgesia, side-effects and analgesic consumption of patients in the postoperative period of heart surgery using intravenous PCA incontinuous infusion plus morphine bolus. Method: Prospective study carried out in a hospital of São Paulo. Patients were followed-up as from extubation every 6 h,until 30h. The following variables were evaluated: pain intensity, analgesic consumption, lumber of analgesic requests and side effects. Results: There has been no pain in 86 per cent of patients. Predominant side-effects were nausea and vomiting with significant decrease in morphine consumption and request. Conclusion: Continuous infusion plus bolus is safe and effective to control pain.

The opioid peptide nociceptin/orphanin FQ mediates prostaglandin E2-induced allodynia, tactile pain associated with nerve injury.

Pain often outlasts its usefulness as warning and aid in wound healing, and becomes chronic and intractable after tissue damage and nerve injury. Many molecules have been implicated as mediators and modulators in persistent pain such as hyperalgesia and tactile pain (allodynia). We previously showed that prostaglandin (PG) E(2), PGF(2alpha) or the neuropeptide nociceptin, also called orphanin FQ (N/OFQ) administered intrathecally (i.t.) produced allodynia in conscious mice. In the present study, we examined the relationship of pain responses between PGs and N/OFQ using the N/OFQ receptor (NOP) antagonist, N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxy-methyl)benzamide monohydrochloride (JTC-801), and in mice lacking the N/OFQ prepropeptide (ppN/OFQ(-/-)) and the NOP receptor (NOP(-/-)). JTC-801 dose-dependently blocked the N/OFQ- and PGE(2)-induced allodynia, but not the PGF(2alpha)-induced one. Neither N/OFQ nor PGE(2) induced allodynia in NOP(-/-) mice. By contrast, the N/OFQ-induced allodynia was not affected by inhibition of PG production by a 60-min pretreatment with the non-steroidal anti-inflammatory drug, indomethacin. Among PGE receptor (EP) subtype-selective agonists, the EP4 agonist, AE1-329, markedly stimulated the release of N/OFQ from spinal slices and induced allodynia. AE1-329 also increased nitric oxide production in spinal slices using fluorescent nitric oxide detection, which was blocked by pretreatment with JTC-801. Conversely, PGE(2)-induced allodynia was not observed in ppN/OFQ(-/-) mice. N/OFQ immunoreactive puncta were colocalized with EP4. Taken together, these results demonstrate that PGE(2) induced allodynia by stimulation of N/OFQ release in the spinal cord via EP4 receptor subtypes.

Chronic administration of nalmefene leads to increased food intake and body weight gain in mice.

Nalmefene is an orally available opioid receptor antagonist that has been shown to suppress appetite in humans, but its effects on chronic food intake and body weight remain unclear. Here, we report that chronic (21-day) oral administration of nalmefene at 2 or 10 mg/kg/day in diet-induced obese (DIO) mice led to significant increases (9-11%) in cumulative food intake. Mice in the nalmefene-treated groups also gained body weight at a rate faster than the control. Body composition analysis showed that the extra body weight gains in the treated animals were mostly due to increased fat accumulation. Since acute nalmefene treatment showed a trend toward a decrease rather than an increase in food intake, it is possible that the orexigenic effect of chronic oral administration of nalmefene was caused by pharmacologically active metabolites rather than the drug itself. Our results argue against the potential use of nalmefene for treating human obesity.

Evidence in locomotion test for the functional heterogeneity of ORL-1 receptors.

1. The ORL1 agonists nociceptin and Ro 64-6198 were compared in their ability to modify spontaneous locomotor activity in male NMRI mice not habituated to the test environment. 2. Higher doses of nociceptin (>5 nmol i.c.v.) reduced whereas lower doses (<1 nmol i.c.v.) stimulated locomotor activity. Both effects were blocked by the putative ORL1 antagonists [NPhe1]nociceptin(1-13)NH2 (10 nmol i.c.v.) and UFP101 (10 nmol, i.c.v.). The effects were also blocked by naloxone benzoylhydrazone (1 mg x kg(-1) s.c.), but not by the nonselective opioid antagonist naloxone (1 mg x kg(-1) s.c.). 3 In contrast to nociceptin, the synthetic ORL1 agonist Ro 64-6198 (0.01-1.0 mg x kg(-1) i.p.) produced monophasic inhibition of locomotor activity, which was insensitive to the treatment with [NPhe1]nociceptin(1-13)NH2 or naloxone benzoylhydrazone. Treatment with UFP101 abolished the locomotor inhibition induced by Ro 64-6198 (1.0 mg x kg(-1)), whereas naloxone (1.0 mg x kg(-1), s.c.) further increased the locomotor-inhibitory effects. 4. Naloxone benzoylhydrazone (0.3; 1.0 and 3.0 mg x kg(-1) s.c.) increased locomotor activity, although the effect was statistically significant only with the highest dose used. 5. Pretreatment with the tyrosine hydroxylase inhibitor H44-68 totally eliminated the motor-stimulatory effects of low doses of nociceptin, probably via dopamine depletion. 6. The results suggest that nociceptin stimulates locomotor activity at low doses if dopamine activity is intact. High doses of nociceptin and all the tested doses of Ro 64-6198 seem to interact with a functionally different subset of ORL1 receptors. In addition, the effects of Ro 64-6198 are modulated by tonic opioid receptor activity.

Morphine administration selectively facilitates social play in common marmosets.

Common marmosets (Callithrix jacchus) form extended families, and several cohorts of young may reside together. Play is shown extensively among the offspring. We hypothesized that opiate activity modulates social play, and predicted that administration of morphine (0.5 mg/kg) would facilitate social play, whereas pretreatment with naloxone (0.5 mg/kg) would block morphine's effects. Morphine administration was associated with significantly increased social play, and the effect of morphine was attributable to the focal subject, since play initiated by others was unaffected by treatment. Non-social categories of play, such as object manipulation and locomotor play, and affiliative behaviors, such as time spent huddled, were unaffected by treatment. Twittering and play face, behaviors used by young during play, also increased after morphine administration. Pretreatment with naloxone blocked morphine's effects. Total activity was significantly increased by morphine administration. We conclude that social play is specifically facilitated by opiate activation, whereas other categories of play behavior and social behavior were unaffected by morphine. Thus, social play represents a distinct category of social behavior in juvenile common marmosets with regulatory processes that are unique from other types of social behavior.

Opioid receptor stimulation acts as mediator of protection in ischaemic preconditioning.

Involvement of the opioid receptors in preconditioning-induced protection has recently been described. The aims of this study were to establish whether: (i) opioid receptor stimulation acts as a trigger ( during the preconditioning protocol) or as a mediator ( during sustained ischaemia) of cardioprotection using either morphine or [D-ala(2), D-leu(5)] enkephalin (DADLE), a synthetic delta-opioid receptor agonist; ( ii) the beneficial effects of DADLE are protein kinase C ( PKC) -mediated; and (iii) inhibitory 'cross-talk' occurs between the beta-adrenergic and phosphatidylinositol pathways activated by release of endogenous catecholamines and opioids respectively during sustained ischaemia. The isolated, perfused working rat heart, subjected to 25 minutes' global ischaemia and 30 minutes' reperfusion, was used as the experimental model. The results showed that delta-opioid receptor stimulation with DADLE (10(-8) M), when administered for 3 x 5 minutes, had no effect, while when given 10 minutes before sustained ischaemia the drug significantly improved functional recovery during reperfusion. This indicates that opioid receptor stimulation acts as a mediator rather than a trigger in the protection elicited. Morphine ( 3 x 10(-7)) when administered in the same manner was without effect. Opioid receptor stimulation caused a marked reduction in the beta -adrenergic response to isoproterenol, indicating inhibitory cross-talk between the phosphatidyl-inositol and beta-adrenergic signal transduction pathways. However, reduction of the beta-adrenergic response to ischaemia does not appear to be the mechanism of opioid-induced protection, as indicated by 3',5' -cyclic adenosine monophosphate (cAMP) levels at the end of 25 minutes' global ischaemia. Opioid receptor-mediated protection against ischaemic damage is PKC-dependent, since DADLE-induced protection could be abolished by the inhibitor chelerythrine.

Supraspinal hyperalgesia and spinal analgesia by [Phe1psi(CH2-NH)Gly2]nociceptin-(1-13)-NH2 in rat.

[Phe1psi(CH2-NH)Gly2]nociceptin-(1-13)-NH2, a pseudopeptide analog of nociceptin, was originally seen as an antagonist of nociceptin receptors. In the present study, it was observed that intracerebroventricular (i.c.v.) injection of this pseudopeptide (1, 5, 10 microg) significantly decreased the tail-flick latency of rats, indicating a hyperalgesic effect, while intrathecal (i.t.) injection of it (1, 2.5, 10 microg) dramatically increased the tail-flick latency, indicating an analgesic effect. This strengthened the in vivo evidence that [Phe1psi(CH2NH)Gly2]nociceptin-(1-13)-NH2 might be an agonist of nociceptin receptors.