Pain control by immune-derived opioids

1. The nervous and immune systems communicate with each other by use of cytokines and neuropeptides. 2. Interactions between immune cell-derived opioid peptides and opioid receptors located in peripheral inflamed tissue lead to endogenous analgesia. 3. In addition to their immunological functions, immunocytes are involved in intrinsic pain inhibition. This provides new insights into pain associated with a compromised immune system, as in AIDS or in cancer. 4. The activation of opioid production and release from immune cells may be a novel approach to the development of peripherally acting analgesics. Because such drugs would be targeted towards events in peripheral injured tissue, these analgesics should lack unwanted central side effects typically associated with opioids.     

Viewing chemokines as a third major system of communication in the brain

There is irrefutable proof that opioids and other classes of centrally acting drugs have profound effects on the immune system. Evidence is mounting that products of the immune system, such as chemokines, can reciprocally alter the actions of these drugs and the endogenous ligands for their receptors. Chemokines are a family of small (8 to 12 kDa) proteins involved in cellular migration and intercellular communication. With a few exceptions, they act on more than one receptor. Although the chemokines and their G protein-coupled receptors are located in both glia and neurons throughout the brain, they are not uniformly distributed. They are found in such brain areas as the hypothalamus, nucleus accumbens, limbic system, hippocampus, thalamus, cortex, and cerebellum. Among the chemokines differentially localized in brain neurons and glia are CCL2/MCP-1, CXCL12/SDF-1alpha, CX3CL1/fractalkine, CXCL10/IP 10, CCL3/MIP-1alpha, and CCL5/RANTES. Functional roles for the chemokine system, composed of the chemokine ligands and their receptors, have been suggested in brain development and heterologous desensitization. The system can alter the actions of neuronally active pharmacological agents such as opioids and cannabinoids and interact with neurotransmitter systems. In this review, we propose that the endogenous chemokine system in the brain acts in concert with the neurotransmitter and neuropeptide systems to govern brain function. It can thus be thought of as the third major system in the brain.     

Effect of adding ketorolac to intravenous morphine patient-controlled analgesia on bowel function in colorectal surgery patients--a prospective, randomized, double-blind study

BACKGROUND: Postoperative ileus (PI) is the transient impairment of bowel motility due to surgical trauma and the associated physiological responses. Postoperative ileus results in patient discomfort, increases gastrointestinal risks, prolongs hospital stay and increases medical expenses. In this study, we investigated the effect of patient-controlled analgesia (PCA) morphine with or without ketorolac on bowel functions in patients after colorectal surgeries. METHODS: A total of 79 patients who received elective colorectal resection were randomly allocated into two groups receiving either intravenous PCA morphine (M group) or intravenous PCA morphine plus ketorolac (K group). Recovery of bowel functions (bowel movement, passage of flatus, and soft diet intake), pain scores, morphine consumption, time for first ambulation, and opioid-related side-effects were recorded. RESULTS: Patients in the K group received 29% less morphine than patients in the M group with comparable pain scores. The first bowel movement (1.5 [0.7-1.9] vs. 1.7 [1.0-2.8] days, P < 0.05) and the first ambulation (2.2 +/- 1.0 vs. 2.8 +/- 1.2 days, P < 0.05) were significantly earlier in the K group than in the M group. The time of the first flatus passing, the first intake of soft diet, and duration of hospital stay were not significantly different between the two groups. CONCLUSIONS: The results of this study suggest that addition of ketorolac to intravenous morphine PCA provides an opioid-sparing effect but has limited benefit in shortening the duration of bowel immobility and time to first ambulation. These findings imply that postoperative ileus is attributable to multiple factors in addition to morphine consumption.     

Naloxone administration and ventilation in awake cats

Naloxone, an opiate antagonist, was administered to unrestrained awake cats to determine whether endogenous opioids tonically inhibit breathing. Whole body plethysmography was used to assess ventilation. Minute ventilation, tidal volume and breathing frequency were determined in each of 4 cats before and after 0.4 and 4.0 mg/kg naloxone. Analysis of variance did not show a significant difference between ventilatory values obtained before and after naloxone administration. Similarly, end-tidal pCO2 did not change systematically throughout a given trial.     

Context and process of informed consent for pharmacologic strategies in labor pain care

The care of women experiencing labor pain often challenges midwives to provide ethical informed consent for the pharmacologic strategies common in most of America's childbearing environments. A systematic approach to this clinical dilemma begins with a conceptual understanding of the origins of labor pain stimuli, factors affecting their central nervous system processing, and the differentiation of the concepts of pain, suffering, and comfort. These concepts can be integrated into a labor pain care, rather than pain management, model for clinical practice. Because most midwives provide care for laboring women in acute care hospitals, the midwife must also understand how the standards of the Joint Commission on Accreditation of Healthcare Organizations influence the behavior of other professionals in the health care environment for laboring women and the process of informed consent. A systematic approach to informed consent for pharmacologic strategies for labor pain care strategies should begin during pregnancy and includes full, unbiased disclosure of the nature, benefits, risks, side effects, and efficacy of all methods that are available in the chosen birth setting.     

Intrathecal fentanyl and sufentanil added to bupivacaine augments analgesia after surgical repair of hip fracture

The aim of our study was to assess efficacy and safety of intrathecal fentanyl and sufentanil added to bupivacaine for surgical repair of fractured hip in patients over 60 years. After standard premedication group C was administered bupivacaine 0.5% 3 ml+saline 1 ml, group F bupivacaine 0.5% 3 ml+fentanyl 50 μg/1 ml and group S bupivacaine 0.5% 3 ml+sufentanil 5 μg/l ml. Time to request for analgesia and side-effects were recorded. Duration of analgesia was longer in both opioid groups compared to control (5.4 h, P<0.001), and longer in S (9.5 h) than in F (8.1 h, P<0.05). There were no differences in bradycardia, hypotension, peripheral oxygen saturation below 90% and pruritus among groups. Postoperative nausea and vomiting were higher in F compared to C and S (P<0.05). Intrathecal fentanyl and sufentanil in our study significantly prolonged time to first request for analgesia and were safe to use even in old patients. Sufentanil appears to be more convenient because of longer analgesia and less postoperative nausea and vomiting.     

Effect of varying doses of fentanyl with low dose spinal bupivacaine for caesarean delivery in patients with pregnancy-induced hypertension

The purpose of this study was to evaluate haemodynamic stability, perioperative analgesia and neonatal outcome following intrathecal 0.5% bupivacaine 7.5 mg with varying doses of fentanyl, in parturients with pregnancy-induced hypertension. Forty-five parturients with pregnancy-induced hypertension scheduled for caesarean section were randomly allocated to receive 7.5 mg bupivacaine with saline 1 mL (group B), fentanyl 10 microg (group Bf10) or fentanyl 20 microg (group Bf20) intrathecally. Heart rate, blood pressure, and sensory block were recorded at regular intervals. Pain, nausea, vomiting, pruritus or any other side effects were sought. Neonatal outcome was assessed using Apgar score and umbilical artery blood gas analysis. Adequate surgical anaesthesia was established in all three groups. There was a statistically significant fall in mean arterial pressure in all three groups within 4-6 min of subarachnoid block (P<0.05), but the decrease in MAP was <20% of baseline in all three groups. Pain and discomfort during surgery were experienced more frequently in group B than in groups Bf10 and Bf20 (P<0.05). Duration of postoperative analgesia was significantly longer in group Bf20 (5.55+/-1.18 h) than in group Bf10 (3.97+/-2.12 h) and group B (3.27+/-1.8 h) (P<0.05). Neonatal outcome was similar in the three groups. Intrathecal fentanyl with low dose bupivacaine provides good surgical anaesthesia and prolongs the duration of analgesia without haemodynamic or neonatal compromise in patients with pregnancy-induced hypertension undergoing caesarean delivery.     

Decreased plasma membrane targeting of NMDA-NR1 receptor subunit in dendrites of medial nucleus tractus solitarius neurons in rats self-administering morphine

Opioid abuse is associated with repeated administration and escalation of dose that can result in profound adaptations in homeostatic processes. Potential cellular mechanisms and neural sites mediating opiate-dependent adaptations may involve NMDA-dependent synaptic plasticity within brain areas participating in behaviors related to consumption of natural reinforcers, as well as affective-autonomic integration, notably the medial nucleus tractus solitarius (mNTS). NMDA-dependent synaptic plasticity may be mediated by changes in the intracellular and surface targeting of NMDA receptors, particularly in postsynaptic sites including spines or small distal dendrites. High-resolution immunogold electron microscopic immunocytochemistry combined with morphometry were used to measure changes in targeting of the NMDA-NR1 (NR1) receptor subunit between intracellular and plasmalemmal sites in dendrites of neurons of the intermediate mNTS of rats self-administering escalating doses of morphine (EMSA). In control and EMSA rats, the density of plasmalemmal and cytosolic gold particles was inversely related to profile size. Collapsed across all NR1-labeled dendrites, rats self-administering morphine had a lower number of plasmalemmal gold particles per unit surface area (7.1 +/- 0.8 vs. 14.4 +/- 1 per 100 microm), but had a higher number of intracellular gold particles per unit cross-sectional area (169 +/- 6.1 vs. 148 +/- 5.1 per 100 microm2) compared to saline self-administering rats. Morphometric analysis showed that the decrease in plasma membrane labeling of NR1 was most robust in small dendritic profiles (<1 microm), where there was a reciprocal increase in the density of intracellular particles. These results indicate that the plasmalemmal distribution of the essential NR1 subunits in distal sites may prominently contribute to NMDA receptor-dependent modulation of neural circuitry regulating homeostatic processes, and targeting of these proteins can be prominently affected by morphine self-administration.     

Effect of intra-operative magnesium sulphate on pain relief and patient comfort after major lumbar orthopaedic surgery

The effects of intra-operative magnesium sulphate on pain relief after major lumbar surgery were investigated in 24 patients. Patients were randomly allocated to receive either an infusion of 50 mg x kg(-1) magnesium sulphate or an equivalent volume of saline at induction of anaesthesia. Anaesthesia was induced with propofol and remifentanil. Tracheal intubation was facilitated using rocuronium. Maintenance was achieved with remifentanil and sevoflurane in nitrous oxide/ oxygen. Intra-operative monitoring included standard equipment and neuromuscular transmission. During surgery, neuromuscular block recovery was longer in the magnesium group. Postoperative opioid consumption and pain scores were lower in the magnesium group. The first night's sleep and the global satisfaction scores were better in the magnesium group. The results of the study support magnesium sulphate as a useful adjuvant for postoperative analgesia after major lumbar surgery.     

The role of the interaction between endogenous opioids and nitric oxide in the pathophysiology of ethanol-induced gastric damage in cholestatic rats

Interaction between endogenous opioids and nitric oxide (NO) has been shown in different biological models and pharmacological evidence suggest that opioids can induce NO release in endothelium as well as in neural cells. Cholestasis is associated with NO overproduction. The reason for increased NO synthesis is not clearly known but it can potentiate development of gastric mucosal damage in cholestatic subjects. Based on increased plasma levels of endogenous opioids and existence of NO overproduction in cholestasis, the present experiments were performed to investigate the role of interaction between endogenous opioids and NO in generation of ethanol-induced gastric damage in cholestatic rats. Cholestasis was induced by surgical ligation of bile duct and sham-operated rats served as controls. The animals received either 20 mg/kg of naltrexone or saline for 6 days and then were fasted and received L-arginine (200 mg/kg), NG-nitro-L-arginine methylester (L-NAME; 2, 5 and 10 mg/kg) or saline. The ethanol-induced gastric mucosal damage was significantly more severe in cholestatic rats than in sham-operated animals (115 +/- 12 mm2 vs. 72 +/- 11 mm2, P < 0.05). L-NAME significantly enhanced the development of gastric mucosal lesions in sham-operated rats. But in cholestatic animals, L-NAME decreased and L-arginine enhanced the severity of gastric damage. Pretreatment of animals with naltrexone decreased severity of gastric mucosal damage in cholestatic rats. Concurrent administration of naltrexone with L-arginine was protective against ethanol-induced gastric damage in both normal and cholestatic groups. Administration of naltrexone with L-NAME had the same effect in cholestatic and control rats and increased severity of gastric damage. Plasma levels of NO2- + NO3- were significantly higher in cholestatic rats than control animals (72 +/- 6 microM vs. 39 +/- 3 microM, P < 0.05). Pretreatment of animals with naltrexone significantly reduced plasma levels of NO2- + NO3- in cholestatic animals, but not in control rats (33 +/- 6 microM vs. 32 +/- 4 microM). The protective effect of L-NAME against gastric damage in cholestatic rats can be explained by inhibition of NO overproduction and it seems that interaction between opioids and NO may have an important role in generation of NO overproduction and gastric complications in cholestatic rats.