A(1) or A(3) adenosine receptors induce late preconditioning against infarction in conscious rabbits by different mechanisms.

We investigated whether activation of A(1) or A(3) adenosine receptors (ARs) induces late preconditioning (PC) against infarction in conscious rabbits using the selective AR agonists 2-chloro-N(6)-cyclopentyladenosine (CCPA) and N(6)-3-iodobenzyladenosine-5'-N-methylcarboxamide (IB-MECA). In vitro radioligand binding and cAMP assays demonstrated CCPA to be approximately 200- to 400-fold selective for the rabbit A(1)AR and IB-MECA to be approximately 20-fold selective for the rabbit A(3)AR. We observed that (1) pretreatment of rabbits 24 hours earlier with CCPA (100 microgram/kg IV bolus) or IB-MECA (100 or 300 microgram/kg) resulted in an approximately 35% to 40% reduction in the size of the infarct induced by 30 minutes of coronary artery occlusion and 72 hours of reperfusion compared with vehicle-treated rabbits, whereas pretreatment with the selective A(2A)AR agonist CGS 21680 (100 microgram/kg) had no effect; (2) the delayed cardioprotective effect of CCPA, but not that of IB-MECA, was completely blocked by coadministration of the highly selective A(1)AR antagonist N-0861; (3) inhibition of nitric oxide synthase (NOS) with N(omega)-nitro-L-arginine during the 30-minute occlusion abrogated the infarct-sparing action of CCPA but not that of IB-MECA; and (4) inhibition of ATP-sensitive potassium (K(ATP)) channels with sodium 5-hydroxydecanoate during the 30-minute occlusion blocked the cardioprotective effects of both CCPA and IB-MECA. Taken together, these results indicate that activation of either A(1)ARs or A(3)ARs (but not A(2A)ARs) elicits delayed protection against infarction in conscious rabbits and that both A(1)AR- and A(3)AR-induced cardioprotection involves opening of K(ATP) channels. However, A(1)AR-induced late PC uses an NOS-dependent pathway whereas A(3)AR-induced late PC is mediated by an NOS-independent pathway.

Targeted deletion of the A3 adenosine receptor confers resistance to myocardial ischemic injury and does not prevent early preconditioning.

We used mice with genetic disruption of the A3 adenosine receptor (AR) gene (A3AR(-/-)mice) to assess the in vivo role of the A3AR in modulating myocardial ischemia/reperfusion injury and preconditioning (PC). Surprisingly, infarct size induced by 30 min of coronary artery occlusion and 24 h of reperfusion was 35% smaller in A3AR(-/-)compared to wild-type mice (A3AR(+/+)). The reduction in infarct size was not the result of differences in heart rate, body temperature or increased cardiac expression of A1ARs. However, neutrophil infiltration within infarcted regions was less in A3AR(-/-)mice. Furthermore, ischemic PC induced by either a single episode (one 5 min occlusion) or multiple episodes (six 4 min occlusions) of ischemia produced equivalent reductions in infarct size in A3AR(-/-)and A3AR(+/+)mice. These results indicate that, in the mouse, (i) A3ARs play an injurious role during acute myocardial ischemia/reperfusion injury, possibly by exacerbating the inflammatory response, and (ii) A3ARs are not necessary for the development of the early phase of ischemic PC.

PKC-dependent activation of p44/p42 MAPKs during myocardial ischemia-reperfusion in conscious rabbits.

Using conscious rabbits, we examined the effect of ischemic preconditioning (PC) on p44 and p42 mitogen-activated protein kinases (MAPKs). We found that both isoforms contribute significantly to total MAPK activity in the heart (in-gel kinase assay: p44, 59 +/- 1%; p42, 41 +/- 1%). Ischemic PC (6 cycles of 4-min occlusion/4-min reperfusion) elicited a pronounced increase in total cellular MAPK activity (+89%). This increase, which occurred exclusively in the nuclear fraction, was contributed by both isoforms (in-gel kinase assay: p44, +97%; p42, +210%) and was accompanied by migration of the two proteins from the cytosolic to the nuclear compartment. In control rabbits, MAPK kinase (MEK)1 and MEK2, direct activators of p44 and p42 MAPKs, were located almost exclusively in the cytosolic fraction. Ischemic PC induced a marked increase in cytosolic MEK activity (+164%), whereas nuclear MEK activity did not change, indicating that MEK-induced activation of MAPKs occurred in the cytosolic compartment. Activation of MAPKs after ischemic PC was completely blocked by the protein kinase C (PKC) inhibitor chelerythrine. Selective overexpression of PKC-epsilon in adult rabbit cardiomyocytes induced activation of both p44 and p42 MAPKs and reduced lactate dehydrogenase release during simulated ischemia-reperfusion, which was abolished by the MEK inhibitor PD-98059. The results demonstrate that 1) ischemic PC induces a rapid activation of p44 and p42 MAPKs in hearts of conscious rabbits; 2) the mechanism of this phenomenon involves activation of p44 and p42 MAPKs in the cytosol and their subsequent translocation to the nucleus; and 3) it occurs via a PKC-mediated signaling pathway. The in vitro data implicate PKC-epsilon as the specific isoform responsible for PKC-induced MAPK activation and suggest that p44/p42 MAPKs contribute to PKC-epsilon-mediated protection against simulated ischemia. The results are compatible with the hypothesis that p44 and p42 MAPKs may play a role in myocardial adaptations to ischemic stress.

Neural blockade for abdominopelvic pain of oncologic origin.

Neural blockade, like other accepted treatments for persistent pain, is not a panacea. Careful assessment is required to elicit the need for complementary interventions, including pharmacological management and psychobehavioral and rehabilitative approaches, combined with attention to the palliation of other symptoms. Celiac and superior hypogastric plexus blocks are well-accepted, effective, and minimally hazardous means for providing palliation of visceral abdominopelvic pain. Although they require radiological imaging, they are relatively undemanding of the experienced anesthesiologist pain specialist and do not deplete patients' limited resources and energy. Because of their uniquely favorable risk:benefit ratio, these procedures should be considered early in the course of treating patients with abdominopelvic pain that is expected to persist.

The MMPI and chronic pain: the diagnosis of psychogenic pain.

This study investigates the capacity of the MMPI to discriminate among groups of patients with different types of pain. When multivariate analysis of variance is used, the standard set of MMPI scales discriminates between acute pain and chronic pain but not between chronic pain of two different etiologies (surgical-iatrogenic vs. unknown). The three scales that discriminate acute from chronic pain patients are those in the "neurotic triad," Hs, D, and Hy. The possibility that the unknown pain etiology group could be broken down into psychogenic pain and undetected somatogenic pathology subgroups was explored using cluster analysis. This procedure did not yield any group of patients who could be identified as having chronic pain of psychogenic origin. These results suggest that the MMPI is not a reliable tool for the differential diagnosis of chronic pain. It appears, however, that patterns of findings are partly contingent on population characteristics. Researchers should be cautious about generalizing to populations other than those from which samples are drawn.

Percutaneous radiofrequency trigeminal gangliolysis in the treatment of tic douloureux.

The treatment of tic douloureux was dramatically altered in 1962 with the demonstration that carbamazepine (Tegretol(R)) alone or in combination with diphenylhydantoin sodium (Dilantin(R)) was effective in controlling the painful paroxysms. However, 30 percent of the patients so treated have not been successfully managed and some type of surgical therapy is required to control their pain. A wide variety of surgical alternatives are available but they all trade a sensory deficit for pain relief and have a significant risk of morbidity and mortality. Experience with percutaneous radiofrequency trigeminal gangliolysis has indicated that this new technique is capable of producing lasting relief of tic douloureux in as many as 95 percent of the patients. To date there have been no deaths from this procedure and a very low incidence of minor complications. It achieves this high success rate at the expense of only partial sensory deficits restricted to a circumscribed area of the face. No other surgical alternative carries such a high long-term success rate with a low complication rate. We believe that percutaneous radiofrequency trigeminal gangliolysis has become the surgical treatment of choice for tic douloureux.

Diagnostic and therapeutic blocks in pain therapy.

The skillful use of nerve blocks is important as a diagnostic, prognostic, and therapeutic tool in the management of chronic and acute pain problems. It is important that these blocks be performed not as technical exercises, but with responsibility, skill, and understanding--and in collaboration with both the patient and fellow physicians, so as to minimize or avoid harmful side effects and give the earliest possible relief from suffering.

Relief of pain by transcutaneous stimulation.

A series of 198 patients with chronic pain of diverse etiology was carefully analyzed for epidemiologic and descriptive factors which might influence the response to transcutaneous stimulation. The overall series included 12 1/2% with long-term success, and 68% with partial or short-term relief. There were no consistent specific diagnoses, or epidemiologic or descriptive factors that made good results from stimulation predictable. Stimulation of the painful area itself was not always necessary for pain relief. Favorable responses to transcutaneous stimulation were usually correlated with the continued existence of significant sensory input from the painful region. The authors conclude that transcutaneous stimulation is a valuable therapeutic modality for some patients with chronic pain.