Chong Chi Chiu

Treadmill Training Combined with Insulin Suppresses Diabetic Nerve Pain and Cytokines in Rat Sciatic Nerve

BACKGROUND:Insulin therapy plays a critical role in managing type 1 diabetes mellitus, and exercise produces alterations in pain sensation. This experiment explored the effects of insulin therapy combined with treadmill training on diabetic neuropathic pain and on the expression of malondialdehyde (MDA) and cytokines. METHODS:Rats were given 4 weeks of insulin (100 IU/kg) therapy and treadmill training (30–60 min/d of training at 20–25 m/min) each day beginning on day 3 after streptozotocin (65 mg/kg, IV) injection and continuing until day 27. Sensitivity to heat and mechanical stimuli and the expression of interleukin (IL)-10, IL-6, tumor necrosis factor-&agr;, and MDA in the sciatic nerve were estimated. RESULTS:We showed that 2 to 4 weeks of treadmill training, insulin treatment, or their combination increased both paw withdrawal thresholds and latencies compared with the same regimen in sedentary diabetic rats (all P < 0.0022). Treatment with insulin, but without treadmill training, had significant effects on glycemic control (P < 0.0001) and restored body weight (P < 0.0001) in the diabetic rats. The diabetic rats demonstrated the upregulation (all P < 0.009) of IL-6, MDA, and tumor necrosis factor-&agr; in the sciatic nerve on days 14 and 28 after streptozotocin treatment, whereas in diabetic rats receiving insulin, treadmill training, or a combination (all P < 0.01), this upregulation was decreased. Insulin, treadmill training, or the combination increased IL-10 expression (all P < 0.0051) in all diabetic rats. CONCLUSIONS:Treadmill training combined with insulin therapy showed the best improvements in tactile allodynia and thermal hyperalgesia among our 3 treatment groups. The benefits of insulin intervention and treadmill training could be related to chronic inflammation (proinflammatory cytokines) and oxidative stress (MDA).

Subcutaneous L-tyrosine elicits cutaneous analgesia in response to local skin pinprick in rats

The purpose of the study was to estimate the ability of L-tyrosine to induce cutaneous analgesia and to investigate the interaction between L-tyrosine and the local anesthetic lidocaine. After subcutaneously injecting the rats with L-tyrosine and lidocaine in a dose-dependent manner, cutaneous analgesia (by blocking the cutaneous trunci muscle reflex-CTMR) was evaluated in response to the local pinprick. The drug-drug interaction was analyzed by using an isobolographic method. We showed that both L-tyrosine and lidocaine produced dose-dependent cutaneous analgesia. On the 50% effective dose (ED50) basis, the rank of drug potency was lidocaine (5.09 [4.88-5.38] μmol)>L-tyrosine (39.1 [36.5-41.8] μmol) (P<0.05). At the equipotent doses (ED25, ED50, and ED75), the duration of cutaneous analgesia caused by L-tyrosine lasted longer than that caused by lidocaine (P<0.01). Lidocaine co-administered with L-tyrosine exhibited an additive effect on infiltrative cutaneous analgesia. Our pre-clinical study demonstrated that L-tyrosine elicits the local/cutaneous analgesia, and the interaction between L-tyrosine and lidocaine is additive. L-tyrosine has a lower potency but much greater duration of cutaneous analgesia than lidocaine. Adding L-tyrosine to lidocaine preparations showed greater duration of cutaneous analgesia compared with lidocaine alone.

Propranolol combined with dopamine has a synergistic action in intensifying and prolonging cutaneous analgesia in rats

BACKGROUNDnThe purpose of the experiment was to assess interactions of dopamine with propranolol as an infiltrative anesthetic.nnnMETHODSnAfter injecting the rats with four doses of drugs subcutaneously, the cutaneous analgesic effect of propranolol was compared with dopamine through the blockade of cutaneous trunci muscle reflex (CTMR) in response to local skin pinprick. Drug-drug interactions were examined via an isobolographic analysis.nnnRESULTSnWe demonstrated that the action of propranolol and dopamine was dose dependent to skin infiltrative analgesia. On the ED(50) (50% effective dose) basis, the rank of drug potency was propranolol (11.3 [10.6-12.2]μmol) > dopamine (195 [188-205]μmol) (p < 0.001). At the equi-anesthetic doses (ED(25), ED(50), ED(75)), the block duration caused by dopamine was equal to that caused by propranolol. Coadministration of dopamine and propranolol exhibited a synergistic effect on infiltrative cutaneous analgesia.nnnCONCLUSIONSnThe preclinical data showed that dopamine produced a lesser potency but a comparable duration of cutaneous analgesia compared to propranolol. Adding dopamine to propranolol potentiated and prolonged propranolols cutaneous analgesic effect.

Memantine elicits spinal blockades of motor function, proprioception, and nociception in rats

Although memantine blocks sodium currents and produces local skin anesthesia, spinal anesthesia with memantine is unknown. The purpose of the study was to evaluate the local anesthetic effect of memantine in spinal anesthesia and its comparison with a widely used local anesthetic lidocaine. After intrathecally injecting the rats with five doses of each drug, the dose—response curves of memantine and lidocaine were constructed. The potencies of the drugs and durations of spinal anesthetic effects on motor function, proprioception, and nociception were compared with those of lidocaine. We showed that memantine produced dose‐dependent spinal blockades in motor function, proprioception, and nociception. On a 50% effective dose (ED50) basis, the rank of potency was lidocaine greater than memantine (P < 0.05 for the differences). At the equipotent doses (ED25, ED50, ED75), the block duration produced by memantine was longer than that produced by lidocaine (P < 0.05 for the differences). Memantine, but not lidocaine, displayed more sensory/nociceptive block than motor block. The preclinical data demonstrated that memantine is less potent than lidocaine, whereas memantine produces longer duration of spinal anesthesia than lidocaine. Memantine shows a more sensory‐selective action over motor blockade.

Ifenprodil for prolonged spinal blockades of motor function and nociception in rats.

BACKGROUNDnThe aim of the study was to compare the proposed spinal anesthetic effect of ifenprodil, an a1 adrenergic receptor antagonist, with that of the long-acting local anesthetic bupivacaine.nnnMETHODSnAfter intrathecally injecting the rats with five different doses of each drug, the dose-response curves of ifenprodil and bupivacaine were constructed to obtain the 50% effective dose (ED50). The spinal blockades of motor function and nociception of ifenprodil were compared with that of bupivacaine.nnnRESULTSnWe showed that either ifenprodil or bupivacaine produced spinal blockades of motor function and nociception dose-dependently. On the ED50 basis, the potency of ifenprodil (0.42(0.38-0.46) μmol; 0.40(0.36-0.44) μmol) was equal (p>0.05) to that of bupivacaine (0.38(0.36-0.40) μmol; 0.35(0.32-0.38) μmol) in motor function and nociception, respectively. At the equianesthetic doses (ED25, ED50, and ED75), duration produced by ifenprodil was greater than that produced by bupivacaine in motor function and nociception (p<0.05 for the differences). Furthermore, both ifenprodil and bupivacaine showed longer duration of sensory blockade than that of motor blockade (p<0.05 for the differences).nnnCONCLUSIONSnThe resulting data demonstrated that ifenprodil produces a dose-dependent local anesthetic effect in spinal anesthesia. Ifenprodil shows a more sensory-selective duration of action over motor block, whereas the duration of anesthesia is significantly longer with ifenprodil than with bupivacaine.

Clonidine as an adjuvant for propranolol enhances its effect on infiltrative cutaneous analgesia in rats.

Clonidine prolongs duration of analgesia when used as an adjunct to local anesthetics for infiltrative cutaneous analgesia, and propranolol produces local anesthesia. The purpose of the experiment was to evaluate clonidine as an adjuvant for propranolol on the quality and duration of cutaneous analgesia. A rat model of cutaneous trunci muscle reflex (CTMR) in response to local skin pinprick was employed to evaluate the cutaneous analgesic effect of propranolol combined with clonidine. The long-lasting local anesthetic bupivacaine was used as control. Cutaneous analgesia elicited by propranolol and bupivacaine was dose-dependent, and both propranolol (9.0μmol) and bupivacaine (1.8μmol) produced 100% nociceptive blockade. On an 50% effective dose (ED50) basis, the relative potency was bupivacaine [0.48 (0.42-0.55) μmol] greater than propranolol [2.27 (1.98-2.54) μmol] (p<0.01). Subcutaneous saline and clonidine (0.12μmol) did not produce cutaneous analgesia. The mixture of an ineffective-dose clonidine (0.12μmol) and a drug (propranolol or bupivacaine) at ED50 or ED95 increased the potency and extended the duration at producing cutaneous analgesia. The resulting data demonstrated that propranolol is less potent than bupivacaine as an infiltrative anesthetic. Clonidine as an adjuvant for propranolol or bupivacaine has a significant peripheral action in increasing the depth and duration of action on infiltrative cutaneous analgesia.

Synergistic Effects of Serotonin or Dopamine Combined With Lidocaine at Producing Nociceptive Block in Rats.

Background The purpose of this experiment was to investigate the interactions of the local anesthetic lidocaine combined with an agent (serotonin or dopamine) as infiltrative anesthetics. Methods Cutaneous analgesia was characterized by the blockade of the cutaneous trunci muscle reflex following 6 skin pinpricks on the rat back. Serotonin or dopamine at producing cutaneous analgesia in a dosage-dependent fashion was compared with lidocaine. Drug-drug interactions were calculated using the isobolographic analysis. Results We revealed that serotonin, dopamine, and lidocaine provoked dose-related cutaneous analgesic effects. On the 50% effective dose basis, the rank of drugs potency was found to be serotonin (1.70 [1.56–1.85] &mgr;mol) > lidocaine (5.18 [4.67–5.75] &mgr;mol) > dopamine (43.0 [40.9–45.2] &mgr;mol) (P < 0.01). At doses equivalent to their 25%, 50%, and 75% effective doses, serotonin or dopamine elicited a longer duration of action than lidocaine (P < 0.01) on producing cutaneous analgesia. Coadministration of serotonin or dopamine with lidocaine produced a synergistic effect. Conclusions The preclinical data showed that serotonin and dopamine produce dose-related cutaneous analgesic effects as an infiltrative anesthetic. Serotonin has a better potency with a much longer duration of action compared with lidocaine at provoking cutaneous analgesia. Serotonin or dopamine as an adjuvant increases the quality of lidocaine in cutaneous analgesia.

Isobolographic analysis of the cutaneous antinociceptive interaction between bupivacaine co-injected with serotonin in rats

BACKGROUNDnThe aim of this experiment was to investigate a long-lasting local anesthetic bupivacaine combined with serotonin at inducing cutaneous antinociception.nnnMETHODSnThe skin antinociception, characterized by an inhibition of the cutaneous trunci muscle reflex (CTMR) following the pinprick on the dorsal skin of rats, was evaluated. The cutaneous antinociceptive effects of bupivacaine alone, serotonin alone, or bupivacaine co-injected with serotonin in a dose-dependent fashion were constructed, while the drug-drug interactions were evaluated by isobologram.nnnRESULTSnSubcutaneous serotonin, as well as the local anesthetic bupivacaine provoked dose-related cutaneous antinociception. On an equipotent basis (50% effective dose [ED50]), the relative potency was bupivacaine (0.43 [0.37-0.50] μmol)>serotonin (1.27 [1.15-1.40] μmol) (p<0.01). At the equi-anesthetic doses (ED75, ED50 and ED25), the duration of bupivacaine was similar to that of serotonin at producing cutaneous antinociceptive effects. Co-administration of bupivacaine and serotonin displayed a synergistic antinociception.nnnCONCLUSIONSnThe preclinical data demonstrated that serotonin is less potent in eliciting cutaneous antinociceptive effects but has the similar duration of action, compared with bupivacaine. We also found a more significant depth of the sensory block with bupivacaine+serotonin than bupivacaine alone.

The addition of epinephrine to proxymetacaine or oxybuprocaine solution increases the depth and duration of cutaneous analgesia in rats

Background The aim of this experiment was to investigate the interaction between epinephrine and 2 local anesthetics (proxymetacaine or oxybuprocaine) using subcutaneous injections under the hairy skin, thereby simulating infiltration blocks. Methods Using a rat model of cutaneous trunci muscle reflex in response to local skin pinpricks, the anesthetic properties of proxymetacaine and oxybuprocaine alone and in combination with epinephrine as an infiltrative anesthetic were tested. Isobolographic analysis was used for the analgesic interactions between adjuvant epinephrine and the local anesthetics. Lidocaine was used as a control group. Results Oxybuprocaine, proxymetacaine, and lidocaine elicited a dose-dependent block to pinpricks. On the 50% effective dose (ED50) basis, their relative potencies were proxymetacaine [0.126 (0.113–0.141) &mgr;mol] greater than oxybuprocaine [0.208 (0.192–0.226) &mgr;mol] greater than lidocaine [6.331 (5.662–7.079) &mgr;mol] (P < 0.01 for each comparison). On an equipotent basis (ED25, ED50, and ED75), sensory block duration elicited by oxybuprocaine or proxymetacaine was greater than that elicited by lidocaine (P < 0.01). Coadministration of proxymetacaine, oxybuprocaine, or lidocaine with epinephrine produced a synergistic analgesic effect and prolonged the cutaneous analgesic effect. After adding epinephrine, oxybuprocaine was much faster, reaching its maximal blockade, than proxymetacaine or lidocaine (P < 0.01). Conclusions We concluded that proxymetacaine and oxybuprocaine were more potent and produced greater duration of nociceptive block than lidocaine. The use of epinephrine augmented the potency and prolonged the duration of proxymetacaine, oxybuprocaine, and lidocaine as an infiltrative anesthetic.

High frequency transcutaneous electrical nerve stimulation with diphenidol administration results in an additive antiallodynic effect in rats following chronic constriction injury

The impact of coadministration of transcutaneous electrical nerve stimulation (TENS) and diphenidol is not well established. Here we estimated the effects of diphenidol in combination with TENS on mechanical allodynia and tumor necrosis factor-α (TNF-α) expression. Using an animal chronic constriction injury (CCI) model, the rat was estimated for evidence of mechanical sensitivity via von Frey hair stimulation and TNF-α expression in the sciatic nerve using the ELISA assay. High frequency (100Hz) TENS or intraperitoneal injection of diphenidol (2.0μmol/kg) was applied daily, starting on postoperative day 1 (POD1) and lasting for the next 13 days. We demonstrated that both high frequency TENS and diphenidol groups had an increase in mechanical withdrawal thresholds of 60%. Coadministration of high frequency TENS and diphenidol gives better results of paw withdrawal thresholds in comparison with high frequency TENS alone or diphenidol alone. Both diphenidol and coadministration of high frequency TENS with diphenidol groups showed a significant reduction of the TNF-α level compared with the CCI or HFS group (P<0.05) in the sciatic nerve on POD7, whereas the CCI or high frequency TENS group exhibited a higher TNF-α level than the sham group (P<0.05). Our resulting data revealed that diphenidol alone, high frequency TENS alone, and the combination produced a reduction of neuropathic allodynia. Both diphenidol and the combination of diphenidol with high frequency TENS inhibited TNF-α expression. A moderately effective dose of diphenidol appeared to have an additive effect with high frequency TENS. Therefore, multidisciplinary treatments could be considered for this kind of mechanical allodynia.