The effects of inflammation and inflammatory mediators on nociceptive behaviour induced by ATP analogues in the rat.
1. We have studied the behavioural effects of intraplantar injections of adenosine 5'-triphosphate (ATP) and related compounds in freely moving rats and investigated whether these nociceptive effects are augmented in the presence of inflammatory mediators. 2. We find that in normal animals ATP and analogues produce dose-dependent nocifensive behaviour (seen as bursts of elevation of the treated hindpaw), and localized thermal hyperalgesia. The rank order of potency was: alpha,beta-methyleneadenosine 5'-triphosphate (alpha,beta-methylene ATP) > 2-methylthioadenosine triphosphate (2-methylthio ATP) > ATP. After neonatal treatment with capsaicin, to destroy small calibre primary sensory neurones, nocifensive behaviour was largely absent. 3. The effects of ATP analogues were assessed in three models of peripheral sensitization: 2 h after dilute intraplantar carrageenan (0.25% w v(-1)); 24 h after irradiation of the hindpaw with ultraviolet (U.V.) B; immediately following prostaglandin E2 (PGE2) treatment. In all models the effect of alpha,beta-methylene ATP was greatly augmented. After carrageenan, significant hindpaw-lifting behaviour activity was induced by injection of only 0.05 nmol of alpha,beta-methylene ATP, some 100 times less than necessary in normal skin. 4. Our data suggest that it is much more likely that endogenous levels of ATP will reach levels capable of exciting nociceptors in inflamed versus normal skin. Our data also suggest the involvement of P2X3 receptor subunits in ATP-induced nociception. (+info)
Role of protein kinase A in the maintenance of inflammatory pain.
Although the initiation of inflammatory pain (hyperalgesia) has been demonstrated to require the cAMP second messenger signaling cascade, whether this mechanism and/or other mechanisms underlie the continued maintenance of the induced hyperalgesia is unknown. We report that injection of adenylyl cyclase inhibitors before but not after injection of direct-acting hyperalgesic agents (prostaglandin E2 and purine and serotonin receptor agonists) resulted in reduction in hyperalgesia, evaluated by the Randall-Selitto paw-withdrawal test. In contrast, injection of protein kinase A (PKA) inhibitors either before or after these hyperalgesic agents resulted in reduced hyperalgesia, suggesting that hyperalgesia after its activation was maintained by persistent PKA activity but not by adenylyl cyclase activity. To evaluate further the role of PKA activity in the maintenance of hyperalgesia, we injected the catalytic subunit of PKA (PKACS) that resulted in hyperalgesia similar in magnitude to that induced by the direct-acting hyperalgesic agents but much longer in duration (>48 vs 2 hr). Injection of WIPTIDE (a PKA inhibitor) at 24 hr after PKACS reduced hyperalgesia, suggesting that PKACS hyperalgesia is not independently maintained by steps downstream from PKA. In summary, our results indicate that, once established, inflammatory mediator-induced hyperalgesia is no longer maintained by adenylyl cyclase activity but rather is dependent on ongoing PKA activity. An understanding of the mechanism maintaining hyperalgesia may provide important insight into targets for the treatment of persistent pain. (+info)
The novel analgesic compound OT-7100 (5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-a]pyrimid ine) attenuates mechanical nociceptive responses in animal models of acute and peripheral neuropathic hyperalgesia.
We investigated the effects of OT-7100, a novel analgesic compound (5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-a]pyrimidi ne), on prostaglandin E2 biosynthesis in vitro, acute hyperalgesia induced by yeast and substance P in rats and hyperalgesia in rats with a chronic constriction injury to the sciatic nerve (Bennett model), which is a model for peripheral neuropathic pain. OT-7100 did not inhibit prostaglandin E2 biosynthesis at 10(-8)-10(-4) M. Single oral doses of 3 and 10 mg/kg OT-7100 were effective on the hyperalgesia induced by yeast. Single oral doses of 0.1, 0.3, 1 and 3 mg/kg OT-7100 were effective on the hyperalgesia induced by substance P in which indomethacin had no effect. Repeated oral administration of OT-7100 (10 and 30 mg/kg) was effective in normalizing the mechanical nociceptive threshold in the injured paw without affecting the nociceptive threshold in the uninjured paw in the Bennett model. Indomethacin had no effect in this model. While amitriptyline (10 and 30 mg/kg) and clonazepam (3 and 10 mg/kg) significantly normalized the nociceptive threshold in the injured paw, they also increased the nociceptive threshold in the uninjured paw. These results suggest that OT-7100 is a new type of analgesic with the effect of normalizing the nociceptive threshold in peripheral neuropathic hyperalgesia. (+info)
Bradykinin B1 and B2 receptors, tumour necrosis factor alpha and inflammatory hyperalgesia.
The effects of BK agonists and antagonists, and other hyperalgesic/antihyperalgesic drugs were measured (3 h after injection of hyperalgesic drugs) in a model of mechanical hyperalgesia (the end-point of which was indicated by a brief apnoea, the retraction of the head and forepaws, and muscular tremor). DALBK inhibited responses to carrageenin, bradykinin, DABK, and kallidin. Responses to kallidin and DABK were inhibited by indomethacin or atenolol and abolished by the combination of indomethacin + atenolol. DALBK or HOE 140, given 30 min before, but not 2 h after, carrageenin, BK, DABK and kallidin reduced hyperalgesic responses to these agents. A small dose of DABK+ a small dose of BK evoked a response similar to the response to a much larger dose of DABK or BK, given alone. Responses to BK were antagonized by HOE 140 whereas DALBK antagonized only responses to larger doses of BK. The combination of a small dose of DALBK with a small dose of HOE 140 abolished the response to BK. The hyperalgesic response to LPS (1 microg) was inhibited by DALBK or HOE 140 and abolished by DALBK + HOE 140. The hyperalgesic response to LPS (5 microg) was not antagonized by DALBK + HOE 140. These data suggest: (a) a predominant role for B2 receptors in mediating hyperalgesic responses to BK and to drugs that stimulate BK release, and (b) activation of the hyperalgesic cytokine cascade independently of both B1 and B2 receptors if the hyperalgesic stimulus is of sufficient magnitude. (+info)
Effect of i.v. ketamine in combination with epidural bupivacaine or epidural morphine on postoperative pain and wound tenderness after renal surgery.
We studied 60 patients undergoing operation on the kidney with combined general and epidural anaesthesia, in a double-blind, randomized, controlled study. Patients were allocated to receive a preoperative bolus dose of ketamine 10 mg i.v., followed by an i.v. infusion of ketamine 10 mg h-1 for 48 h after operation, or placebo. During the first 24 h after surgery, all patients received 4 ml h-1 of epidural bupivacaine 2.5 mg ml-1. From 24 to 48 h after operation, patients received epidural morphine 0.2 mg h-1 preceded by a bolus dose of 2 mg. In addition, patient-controlled analgesia (PCA) with i.v. morphine (2.5 mg, lockout time 15 min) was offered from 0 to 48 h after operation. Patients who received ketamine felt significantly more sedated at 0-24 h, but not at 24-48 h after operation, compared with patients who received placebo (P = 0.002 and P = 0.127, respectively). There were no significant differences in pain (VAS) at rest, during mobilization or cough, PCA morphine consumption, sensory block to pinprick, pressure pain detection threshold assessed with an algometer, touch and pain detection thresholds assessed with von Frey hairs, peak flow or side effects other than sedation. The power of detecting a reduction in VAS scores of 20 mm in our study was 80% at the 5% significance level. We conclude that we were unable to demonstrate an (additive) analgesic or opioid sparing effect of ketamine 10 mg h-1 i.v. combined with epidural bupivacaine at 0-24 h, or epidural morphine at 24-48 h after renal surgery. (+info)
Somatotopic activation of opioid systems by target-directed expectations of analgesia.
We induced specific expectations of analgesia on four different parts of the body to understand how endogenous opioid systems are activated by expectancies. The left hand, right hand, left foot, and right foot were simultaneously stimulated by means of a subcutaneous injection of capsaicin, which produces a painful burning sensation. Specific expectations of analgesia were induced by applying a placebo cream on one of these body parts and by telling the subjects that it was a powerful local anesthetic. In such a way, expectancy of the anesthetic effect was directed only toward the part on which the placebo cream was applied. We found that a placebo analgesic response occurred only on the treated part, whereas no variation in pain sensitivity was found on the untreated parts. If the same experiment was performed after an intravenous infusion of the opioid antagonist naloxone, this highly spatial-specific placebo response was totally abolished, indicating that it was completely mediated by endogenous opioid systems. These findings show that a spatially directed expectation of pain reduction is capable of inducing a specific effect only on the part of the body which is the target of the expectation. Most important, this specific effect is mediated by endogenous opioids, indicating that placebo-activated opioids do not act on the entire body but only on the part where expectancy is directed. This suggests that a highly organized and somatotopic network of endogenous opioids links expectation, attention, and body schema. (+info)
Analgesia-producing mechanism of processed Aconiti tuber: role of dynorphin, an endogenous kappa-opioid ligand, in the rodent spinal cord.
The analgesia-producing mechanism of processed Aconiti tuber was examined using rodents whose nociceptive threshold was decreased by loading repeated cold stress (RCS). The antinociceptive effect of processed Aconiti tuber (0.3 g/kg, p.o.) in RCS-loaded mice was antagonized by pretreatment with a kappa-opioid antagonist, nor-binaltorphimine (10 mg/kg, s.c.), and was abolished by an intrathecal injection of anti-dynorphin antiserum (5 microg). The Aconiti tuber-induced antinociception was inhibited by both dexamethasone (0.4 mg/kg, i.p.) and a dopamine D2 antagonist, sulpiride (10 mg/kg, i.p.), in RCS-loaded mice, and it was eliminated by both an electric lesion of the hypothalamic arcuate nucleus (HARN) and a highly selective dopamine D2 antagonist, eticlopride (0.05 microg), administered into the HARN in RCS-loaded rats. These results suggest that the analgesic effect of processed Aconiti tuber was produced via the stimulation of kappa-opioid receptors by dynorphin released in the spinal cord. It was also shown that dopamine D2 receptors in the HARN were involved in the expression of the analgesic activity of processed Aconiti tuber. (+info)
Antinociceptive mechanism of Gosha-jinki-gan in streptozotocin-induced diabetic animals: role of nitric oxide in the periphery.
Using streptozotocin-induced diabetic mice and rats, we evaluated the antinociceptive mechanism of Gosha-jinki-gan. The antinociceptive effect of Gosha-jinki-gan (0.3 g/kg, p.o.) in diabetic mice, as determined by the tail-pressure test, was inhibited by N(G)-nitro-L-arginine methyl ester (L-NAME; 2, 5 mg/kg, i.p.). When L-NAME (10 microg) or methylene blue (500 microg) was topically administered to the intraplantar area of the hind paw, the region used for the paw-pressure test, the antinociceptive activity of Gosha-jinki-gan (0.3 g/kg, p.o.) in diabetic rats was decreased. These results suggested that the antinociceptive effect of Gosha-jinki-gan partly resulted from the peripheral action of increasingly produced nitric oxide. (+info)