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Inadequate end organ perfusion and tissue hypoxia is an end point of many disease processes in critical illness. Maintenance of blood flow and hence tissue oxygenation is critical to the management of intensive care patients. End organ blood flow is determined by a balance of myocardial factors (stroke volume and heart rate) and vascular factors (vasodilation and constriction). Global blood flow is determined by a balance of neurohormonal factors, with local autoregulation ultimately determining regional flow. Pharmacological manipulation of both the myocardium and vasculature at the level of the autonomic nervous system (via α or β adrenoceptors), myocardium (e.g. calcium sensitization via levosimendan), or locally (e.g. via sympathectomy) is commonly used in anaesthesia to mitigate the effects of critical illness and to maintain organ perfusion, either through increasing vascular tone or cardiac output. This article considers the global control of the system through to local and regional regulation of blood flow, and how the system may be manipulated at every stage.

Pain is a major cause of distress, both physical and psychological and is also associated with increased inpatient hospital stays, poor wound healing and prolonged rehabilitation. Opioids are a mainstay of treatment for acute pain, although they are associated with significant morbidity through adverse effects such as respiratory depression, psychosis, and nausea and vomiting. The non-opiate analgesics avoid some of these effects, although are not panaceas, non-steroidal anti-inflammatory drugs (NSAIDS), for example, are associated with renal and gastric damage, which precludes their use in elderly patients and those with renal impairment. This article reviews the underlying pain pathways and the ways in which these pathways may be modulated in the pursuit of side-effect-free analgesia. Existing medications target these pathways, although there are evolving targets for analgesics. The advantages and disadvantages of the current non-opioid mainstays of treatment are reviewed. Other centrally acting medications, both research (nociceptin, neuropeptides, cannabinoids) and clinical (gabapentin, carbamazepine) are also considered. Combinations of existing analgesics underlie the principles of multimodal analgesia; non-opioid adjuncts are known to reduce postsurgical opioid requirements and improve rehabilitation and discharge. The answer may lie in synergistic dual-acting medications, which are discussed with reference to the COX-inhibiting nitric oxide donors and dual lipoxygenase/cyclooxygenase inhibitors.

Knockout and pharmacological studies demonstrated that the activation of delta opioid peptide (DOP) receptors produces antidepressant-like effects in rodents. Here we report the results obtained with the novel DOP ligand H-Dmt-Tic-NH-CH 2 -Bid (UFP-502). UFP-502 bound with high affinity (p K i 9.43) to recombinant DOP receptors displaying moderate selectivity over MOP and KOP. In CHO hDOP [ 35 S]GTPγS binding and mouse vas deferens experiments, UFP-502 behaved as a potent (pEC 50 10.09 and 10.70, respectively) full agonist. In these preparations, naloxone, naltrindole and N , N (CH 3 ) 2 Dmt-Tic-OH showed similar p A 2 values against UFP-502 and DPDPE and the same rank order of potency. In vivo in mice, UFP-502 mimicked DPDPE actions, producing a significant reduction of immobility time after intracerebroventricular administration in the forced swimming test and a clear antinociceptive effect after intrathecal injection in the tail withdrawal assay. However, while the effects of DPDPE were fully prevented by naltrindole those evoked by UFP-502 were unaffected (tail withdrawal assay) or only partially reversed (forced swimming test). In conclusion, UFP-502 represents a novel and useful chemical template for the design of selective agonists for the DOP receptor.

To date, J-113397 represents the most potent and selective non peptide NOP receptor antagonist widely used in pharmacological studies. However, the synthesis, purification, and enantiomer separation of this molecule, which contains two chiral centers, is rather difficult and low-yielding. Here, we synthesized and tested a series of simplified J-113397 analogues to investigate the importance of the stereochemistry and the influence of the substituents at position 3 of the piperidine nucleus and on the nitrogen atom of the benzimidazolidinone nucleus. The compound coded as Trap-101, an achiral analogue of J-113397, combines a pharmacological profile similar to that of the parent compound with a practical, high-yielding preparation.

A novel ligand for the nociceptin/orphanin FQ (N/OFQ) receptor (NOP), [(pF)Phe(4),Arg(14),Lys(15)]N/OFQ-NH(2) (UFP-102), has been generated by combining in the N/OFQ-NH(2) sequence two chemical modifications, [Arg(14),Lys(15)] and [(pF)Phe(4)], that have been previously demonstrated to increase potency. In vitro, UFP-102 bound with high affinity to the human NOP receptor, showed at least 200-fold selectivity over classical opioid receptors, and mimicked N/OFQ effects in CHO(hNOP) cells, isolated tissues from various species, and mouse cortical synaptosomes releasing 5-hydroxytryptamine. UFP-102 showed similar maximal effects but higher potency (2- to 48-fold) relative to N/OFQ. The effects of UFP-102 were sensitive to NOP-selective antagonists J-113397 [(+/-)-trans-1-[1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one] (pA(2) = 7.75-8.12) and UFP-101 ([Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2))(pA(2) = 6.91-7.33) but not to naloxone, and no longer observed in tissues taken from NOP receptor knockout mice (NOP(-/-)). In vivo, UFP-102 (0.01-0.3 nmol i.c.v.) mimicked the pronociceptive action of N/OFQ (0.1-10 nmol i.c.v.) in the mouse tail withdrawal assay, displaying higher potency and longer lasting effects. The action of UFP-102 was not apparent in NOP(-/-) mice. Similar results were obtained measuring locomotor activity in mice. In conscious rats, UFP-102 (0.05 nmol i.c.v.) produced a marked and sustained decrease in heart rate, mean arterial pressure, and urinary sodium excretion and a profound increase in urine flow rate. These effects were comparable with those evoked by N/OFQ at 5 nmol. Collectively, these findings demonstrate that UFP-102 behaves as a highly potent and selective NOP receptor agonist that produces long-lasting effects in vivo.