Analgesia In Rats Research Articles

ANTINOCICEPTIVE EFFICACY AND SAFETY OF SUBCUTANEOUS TRAMADOL IN CHINCHILLAS (CHINCHILLA LANIGERA)

Tramadol has been demonstrated to provide analgesia in rats and mice and has been increasingly used in other small companion mammals for treatment of moderate to severe pain. Currently no evidence is available that supports the use of tramadol as an effective analgesic in chinchillas. The purpose of this study was to evaluate the antinociceptive efficacy and safety of subcutaneously administered tramadol in chinchillas. Initial dose-escalation studies were performed to determine if dose-dependent adverse effects occur in chinchillas. At 60 mg/kg subcutaneously (SC), but not at lower doses, tramadol induced clinically significant dose-limiting adverse effects, consisting of whole body tremors and facial muscle fasciculation. Therefore, in a subsequent analgesimetry experiment, tramadol was evaluated at a single dose of 10, 20, and 40 mg/kg SC in a randomized, blinded, controlled, complete crossover design. Thermal antinociceptive efficacy was determined by measuring hindlimb withdrawal latencies following a thermal noxious stimulus (Hargreaves’ method) at 0, 1, 2, 4, and 8 hours after drug administration. Changes in daily food intake and fecal output following tramadol administration were measured. At 10 to 40 mg/kg SC no thermal antinociceptive effects could be demonstrated. A self-limiting and transient significant reduction in food intake and fecal output occurred in a dose-dependent manner when tramadol was administered at 20 and 40 mg/kg. Based on the results of this study tramadol cannot be recommended as an analgesic drug in chinchillas.

A voxel-based analysis of neurobiological mechanisms in placebo analgesia in rats

Placebo analgesia is the beneficial effect that follows despite a pharmacologically inert treatment. Modern neuroimaging studies in humans have delineated the hierarchical brain regions involved in placebo analgesia. However, because of the lack of proper approaches to perform molecular and cellular manipulations, the detailed molecular processes behind it have not been clarified. To address this issue, we developed an animal model of placebo analgesia in rats and analyzed the placebo analgesia related brain activity using small-animal neuroimaging method. We show here that gabapentin-based Pavlovian conditioning successfully induced placebo analgesia in neuropathic pain model rats and hierarchical brain regions are involved in placebo analgesia in rats, including the prelimbic cortex (PrL) of the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), ventrolateral periaqueductal gray matter (vlPAG), etc. The functional couplings in placebo responders between the mPFC and vlPAG was interrupted by naloxone, an antagonist of μ opioid receptor. Moreover, both local chemical lesion and microinfusion of naloxone in the mPFC suppressed the placebo analgesia. These results suggest that the intrinsic μ opioid system in the mPFC causally contribute to placebo analgesia in rats, and the small-animal neuroimaging approach could provide important insights toward understanding the placebo effect in great detail.

Heteromerization of \u03bc-opioid receptor and cholecystokinin B receptor through the third transmembrane domain of the \u03bc-opioid receptor contributes to the anti-opioid effects of cholecystokinin octapeptide

Activation of the cholecystokinin type B receptor (CCKBR) by cholecystokinin octapeptide (CCK-8) inhibits opioid analgesia. Chronic opiate treatment leads to an increase in the CCK-8 concentration and thus enhances the antagonism of CCK-8 against opioid analgesia; the underlying molecular mechanisms remain of great interest. In the present study, we validated the colocalization of the μ-opioid receptor (MOR) and CCKBR in pain signal transmission-related spinal cord dorsal horn and dorsal root ganglion neurons of rats. Co-immunoprecipitation (Co-IP) and fluorescence lifetime-imaging-microscopy-based fluorescence resonance energy transfer (FLIM-FRET) assays showed that MOR heteromerized with CCKBR directly in transfected HEK293 cells. Combined with MOR mutant construction, the third transmembrane domain of MOR (TM3MOR) was demonstrated to participate in heteromerization with CCKBR. Receptor ligand binding, ERK phosphorylation and cAMP assays showed that MOR heteromerization with CCKBR weakened the activity of MOR. A cell-penetrating interfering peptide consisting of TM3MOR and TAT (a transactivator of HIV-1) sequences from the N terminal to the C terminal disrupted the MOR–CCKBR interaction and restored the activity of MOR in transfected HEK293 cells. Furthermore, intrathecal application of the TM3MOR-TAT peptide alleviated CCK-8-injection-induced antagonism to morphine analgesia in rats. These results suggest a new molecular mechanism for CCK-8 antagonism to opioid analgesia in terms of G-protein-coupled receptor (GPCR) interaction through direct heteromerization. Our study may provide a potential strategy for pain management with opioid analgesics.

Transdermal Fentanyl Solution Provides Long-term Analgesia in the Hind-paw Incisional Model of Postoperative Pain in Male Rats.

A recently developed transdermal fentanyl solution was hypothesized to be effective for non-invasive postoperative analgesia in rats. Thirty-nine male Sprague-Dawley rats were treated once with 0.1, 0.33 or 1.0 mg/kg transdermal fentanyl solution at the skin of the scruff 1 h prior to subjected to hind-paw surgery, and compared to non-treated animals. All rats were tested for nociceptive response in the electronic von Frey (EVF) test between 1 and 72 h postoperatively, and assessed daily with regards to facial expression, body weight changes and welfare score. Fentanyl treatment at all doses significantly reduced nociceptive response in the EVF test throughout the 72 h of experimentation, reduced facial expressions on all days postoperatively, slightly reduced the body weight and improved postoperative welfare parameters. The present study indicates that transdermal fentanyl solution seems to be an effective, non-invasive and long-lasting analgesic regimen in male rats.

Subcutaneous infiltration of doxylamine on cutaneous analgesia in rats.

We aimed to evaluate the effect of doxylamine, a first generation antihistamine, as a local analgesic agent by comparing its effect to bupivacaine. After blocking the cutaneous trunci muscle reflex (CTMR) by subcutaneous injection of doxylamine, we assessed doxylamine's cutaneous analgesic effect in rats. The dose-related effect and duration of doxylamine on infiltrative cutaneous analgesia were compared with that of bupivacaine. We demonstrated that doxylamine, as well as the local anesthetic bupivacaine produced the cutaneous analgesic effects in a dose-related fashion. At the equipotent dose (50% effective doses (ED50)), the relative potency was bupivacaine (0.41 (0.36-0.48) mmol)> doxylamine (7.39 (6.91-7.91)mmol) (p<0.01). On an equipotent basis (ED25, ED50 and ED75), subcutaneous doxylamine resulted in greater duration of action (p<0.01) than bupivacaine at producing cutaneous analgesia. The result of this experiment indicated that doxylamine has the local anesthetic property less potent than bupivacaine, but its nociceptive block duration is longer than that of bupivacaine at an equianalgesic dose.

Upregulation of (C-X-C motif) Ligand 13 (CXCL13) Attenuates Morphine Analgesia in Rats with Cancer-Induced Bone Pain.

BackgroundThe aim of this study was to investigate the role of chemokine (C-X-C motif) ligand 13 (CXCL13) in morphine tolerance in rats with cancer-induced bone pain (CIBP).Material/MethodsWe established a rat CIBP model and a rat CIBP-morphine tolerance (BM) model. BM rats were intrathecally administered rmCXCL13, neutralizing anti-CXCL13, and normal saline, while the control group rats underwent a sham operation and were injected with normal saline. The morphine analgesia was assessed by measuring mechanical withdrawal threshold (MWT) and mechanical withdrawal duration (MWD) at various time points. The co-expressions of CXCL13 and NeuN were measured by immunofluorescence double-staining. CXCL13 protein and mRNA expressions were detected by Western blot and quantitative real-time polymerase chain reaction (RT-qPCR), respectively.ResultsCompared to the sham-operation (S) group, the BM group showed obviously decreased MWT and increased MWD on Day 9 after CIBP, but obviously increased MWT and decreased MWD on Day 3 after morphine administration; subsequently, the MWT was decreased and MWD was increased (all P<0.05). In comparison with the S+saline group, increased MWT and decreased MWD were observed in BM rats on Day 3 after anti-CXCL13 administration, and obviously decreased MWT and increased MWD were found in BM rats on Day 3 after rmCXCL13 administration (all P<0.05).ConclusionsUp-regulated CXCL13 has a negative role in morphine analgesia in relief of CIBP, which may provide a new target for the management of CIBP.

Electroencephalographic signatures of pain and analgesia in rats.

Pain modulates rhythmic neuronal activity recorded by Electroencephalography (EEG) in humans. Our laboratory previously showed that rat models of acute and neuropathic pain manifest increased power in primary somatosensory cortex (S1) recorded by electrocorticography (ECoG). In this study, we hypothesized that pain increases EEG power and corticocortical coherence in different rat models of pain, whereas treatments with clinically effective analgesics reverse these changes. Our results show increased cortical power over S1 and prefrontal cortex (PFC) in awake, freely behaving rat models of acute, inflammatory and neuropathic pain. Coherence between PFC and S1 is increased at a late, but not early, time point during the development of neuropathic pain. Electroencephalography power is not affected by ibuprofen in the acute pain model. However, pregabalin and mexiletine reverse the changes in power and S1-PFC coherence in the inflammatory and neuropathic pain models. These data suggest that quantitative EEG might be a valuable predictor of pain and analgesia in rodents.

Vitamin C enhances the analgesic effect of gabapentin on rats with neuropathic pain

AimsGabapentin (Gap) relieves neuropathic pain, but it has several adverse effects as well. We aimed to investigate whether vitamin C (VitC) supplementation would reduce the effective dose of Gap for analgesia in rats with chronic constriction injury (CCI). Main methodsRats were randomly assigned to Sham, CCI, VitC, Gap, and VitC+Gap treatment groups. CCI, involving the left sciatic nerve, was induced in all animals except the Sham group. VitC (500mg/kg (body weight)), Gap (10, 30, or 100mg/kg), or VitC (500mg/kg)+Gap (10, 30, or 100mg/kg) were injected intraperitoneally twice daily for a week from 7days after sham or CCI surgery. Mechanical paw withdrawal threshold (PWT), thermal paw withdrawal latency (PWL) and malondialdehyde (MDA) content in serum or spinal cord tissues were all measured. The expression of sodium dependent vitamin C transporter 2 (SVCT2) and glucose transporter 3 (GLUT3) in dorsal root ganglion (DRG) were detected by quantitative real-time PCR, Western blot and immunohistochemistry. Key findingsNo more than 30mg/kg Gap could restore the decrease of PWT or PWL induced by CCI so long as combined with 500mg/kg VitC. For mechanism study, we found that VitC supplementation would remarkedly ameliorate oxidative stress in peripheral blood, and possibly cause a positive feedback in VitC uptake of neurons in DRG by promoting SVCT2 expression. SignificanceVitamin C can enhance gabapentin's analgesic effect. And the underlying mechanism may be concerned with antioxidative responses which were more obvious in peripheral blood than in the neurons.

Peripheral Opioid Receptors Contribute to Exercise‐Induced Analgesia in Rats with Chronic Widespread Pain

Fibromyalgia is characterized by chronic widespread musculoskeletal pain. Exercise has been shown to cause both analgesia and hyperalgesia in patients with fibromyalgia. Evidence suggests endorphins acting on central opioid receptors produce exercise‐induced analgesia, but the role of peripheral opioid receptors has not been investigated. We tested the hypothesis that peripheral opioid receptors contribute to exercise‐induced analgesia in a rat model of fibromyalgia. Chronic widespread pain was induced by acidic saline (pH 4) injections into the right gastrocnemius muscle of female Sprague Dawley rats. Control rats (n=10) then underwent four weeks (5 days/week; 30 min/day) of moderate‐intensity treadmill running. Treated rats (n=5) received injections of naloxone (120 μg), a nonspecific opioid receptor antagonist, in both gastrocnemius muscles prior to running. Mechanical hyperalgesia was quantified by measuring mechanical withdrawal threshold with von Frey filaments before and after each exercise bout. Changes in mechanical withdrawal threshold before and after running for control rats (week 1: 9 ± 5 mN; week 2: 10 ± 5 mN; week 3: 20 ± 5 mN) were significantly different from decreases in mechanical withdrawal threshold in the naloxone‐treated group (week 1: −13 ± 9 mN; week 2: −18 ± 8 mN; week 3: −13 ± 8 mN; all p&lt;0.05). Values for week 4 were not significantly different between control (11 ± 5 mN) and treated (5 ± 6 mN; p&gt;0.05). Findings suggest peripheral opioid receptors contribute to both exercise‐induced analgesia and exercise‐induced hyperalgesia in chronic pain conditions.

DHEA administration modulates stress-induced analgesia in rats

An important aspect of adaptive stress response is the pain response suppression that occurs during or following stress exposure, which is often referred to as acute stress-induced analgesia. Dehydroepiandrosterone (DHEA) participates in the modulation of adaptive stress response, changing the HPA axis activity. The effect of DHEA on the HPA axis activity is dependent on the state and uses the same systems that participate in the regulation of acute stress-induced analgesia. The impact of DHEA on nociception has been studied; however, the effect of DHEA on stress-induced analgesia is not known. Thus, the aim of the present study was to evaluate the effect of DHEA on stress-induced analgesia and determine the best time for hormone administration in relation to exposure to stressor stimulus. The animals were stressed by restraint for 1h in a single exposure and received treatment with DHEA by a single injection before the stress or a single injection after the stress. Nociception was assessed with a tail-flick apparatus. Serum corticosterone levels were measured. DHEA administered before exposure to stress prolonged the acute stress-induced analgesia. This effect was not observed when the DHEA was administered after the stress. DHEA treatment in non-stressed rats did not alter the nociceptive threshold, suggesting that the DHEA effect on nociception is state-dependent. The injection of DHEA had the same effect as exposure to acute stress, with both increasing the levels of corticosterone. In conclusion, acute treatment with DHEA mimics the response to acute stress indexed by an increase in activity of the HPA axis. The treatment with DHEA before stress exposure may facilitate adaptive stress response, prolonging acute stress-induced analgesia, which may be a therapeutic strategy of interest to clinics.

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.

The Addition of Epinephrine to Proxymetacaine or Oxybuprocaine Solution Increases the Depth and Duration of Cutaneous Analgesia in Rats.

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. 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. 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) μmol] greater than oxybuprocaine [0.208 (0.192-0.226) μmol] greater than lidocaine [6.331 (5.662-7.079) μmol] (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). 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.

Clinical, behavioral and antinociceptive effects of crotalphine in horses

ABSTRACT: Crotalphine is a novel analgesic peptide that acts on kappa opioid and delta receptors, causing powerful analgesia in rats submitted to inflammatory, neuropathic or oncologic models of pain. This study evaluated clinical, behavioral and antinociceptive effects caused by crotalphine in horses, employing 18 Arabian horses and it was divided in three phases. In Phase I, "clinical and behavioral effects", crotalphine did not change the latency to urinate and defecate; did not modify the values of cardiac or respiratory rates, intestinal motility and rectal temperature; and did not cause significant ataxia, head, eye and lip ptosis. In Phase II, "antinociceptive effect on intact skin at scapular or ischial region", crotalphine did not cause significant analgesia. In Phase III, "antinociceptive effect on incised skin at scapular or ischial region", crotalphine promoted effective antinociceptive effects for six hours and inhibited hyperalgesia state for three days in the ischial region of horses submitted to incisional model of inflammatory pain, but crotalphine did not evoke relevant analgesic effect on the scapular region. Concluding, intravenous injection of a single dose of crotalphine (3.8ngkg-1) did not cause important clinical or behavioral changes and promotes antinociceptive effect on incised ischial region for seven days in horses. Moreover, crotalphine did not evoke relevant anti nociceptive effect on the scapular region or in intact skin of horses.

Identification and Characterization of GAL-021 as a Novel Breathing Control Modulator.

The authors describe the preclinical pharmacological properties of GAL-021, a novel peripheral chemoreceptor modulator. The ventilatory effects of GAL-021 were characterized using tracheal pneumotachometry (n = 4 to 6), plethysmography (n = 5 to 6), arterial blood gas analyses (n = 6 to 11), and nasal capnography (n = 3 to 4) in naive animals and those subjected to morphine-induced respiratory depression. Morphine analgesia in rats was evaluated by tail-flick test (n = 6). Carotid body involvement in GAL-021 ventilatory effects was assessed by comparing responses in intact and carotid sinus nerve-transected rats. Hemodynamic effects of GAL-021 were evaluated in urethane-anesthetized rats (n = 7). The pharmacological profile of GAL-021 in vitro was investigated using radioligand binding, enzyme inhibition, and cellular electrophysiology assays. GAL-021 given intravenously stimulated ventilation and/or attenuated opiate-induced respiratory depression in rats, mice, and nonhuman primates, without decreasing morphine analgesia in rats. GAL-021 did not alter mean arterial pressure but produced a modest increase in heart rate. Ventilatory stimulation in rats was attenuated by carotid sinus nerve transection. GAL-021 inhibited KCa1.1 in GH3 cells, and the evoked ventilatory stimulation was attenuated in Slo1 mice lacking the pore-forming α-subunit of the KCa1.1 channel. GAL-021 behaved as a breathing control modulator in rodents and nonhuman primates and diminished opioid-induced respiratory depression without compromising opioid analgesia. It acted predominantly at the carotid body, in part by inhibiting KCa1.1 channels. Its preclinical profile qualified the compound to enter clinical trials to assess effects on breathing control disorders such as drug (opioid)-induced respiratory depression and sleep apnea.

Down-regulation of astroglial glutamate transporter-1 in the locus coeruleus impairs pain-evoked endogenous analgesia in rats

Descending noradrenergic inhibition to the spinal cord from the locus coeruleus (LC) is an important endogenous pain-relief mechanism which can be activated by local glutamate signaling. Here we tested whether dysregulation of extracellular glutamate level in the LC induced by down-regulating astroglial glutamate transporter-1(GLT-1) impairs endogenous analgesia. In rats treated with repeated LC injections of GLT-1 selective or non-targeting small interfering RNA (siRNA), a subdermal injection of capsaicin was used to examine noxious stimulation-induced analgesia (NSIA), evoked LC glutamate and spinal noradrenaline release, and evoked LC neuronal activity. LC-injected GLT-1 siRNA reduced expression of GLT-1 in the LC (P=0.02), increased basal activity of LC neurons (P<0.01), and increased basal extracellular concentrations of LC glutamate (P<0.01) and spinal noradrenaline (P<0.01), but did not affect mechanical withdrawal thresholds in the hindpaw (P=0.83), compared to non-targeting siRNA. LC-injected GLT-1 siRNA impaired capsaicin-evoked release of LC glutamate and spinal noradrenaline, capsaicin-evoked LC neuronal activation, and NSIA. These results suggest that astroglial GLT-1 is essential to normal LC function and that increased extracellular glutamate by down-regulating GLT-1 impairs evoked LC activity and NSIA, essentially taking the LC “off-line”.

Preemptive Analgesia with Acupuncture Monitored by c-Fos Expression in Rats

Pain behavior and awareness are characterized by heightened alertness and anxiety, which begin to disappear as soon as the curative process starts. The present study aimed to quantify c-fos expression in rat spinal cords and brains after a surgical stimulus and with preoperative or postoperative acupuncture. Animals were randomly divided into preoperative and postoperative groups and were then further divided into control, manual acupuncture (MA), or electroacupuncture (EA) groups. Expression of c-fos was quantified using immunohistochemistry. The collected data were analyzed using the t test at a 5% probability level. Presurgery and postsurgery spinal cord c-fos expressions were similar in all of the treatment groups. In the control rats, c-fos expression was higher before surgery than after surgery, contradicting the expected outcome of acupuncture and preemptive analgesia. After treatment, the expression of c-fos in the brains of the rats in the MA and the EA groups was reduced compared with that of the rats in the control group. These findings suggest that acupuncture used as preemptive analgesia in rats is a useful model for studying its application in human treatment.

The furoxan nitric oxide donor, PRG150, evokes dose-dependent analgesia in a rat model of painful diabetic neuropathy.

Painful diabetic neuropathy (PDN) is a type of peripheral neuropathic pain that is often intractable. Elevated nitric oxide (NO) from neuronal and non-neuronal sources in the somatosensory system is implicated in the pathobiology of peripheral neuropathic pain. However, in diabetes, nitrergic nerve degeneration to deplete NO bioactivity appears causal in the pathogenesis of irreversible autonomic neuropathy, another long term complication of diabetes. Hence, this study hypothesized that progressive NO depletion may underpin the pathobiology of PDN and that NO donors may alleviate PDN. Diabetes was induced in rats with intravenous streptozotocin (STZ) at 70mg/kg and confirmed if blood glucose levels (BGLs) on day 10 post-STZ were ≥15mmol/L. Analgesic efficacy of subcutaneous (s.c.) bolus doses of the furoxan NO donor, PRG150 was assessed in the STZ-diabetic rat model of PDN at 10-, 14- and 24-weeks post-STZ relative to the sydnominine NO donor, SIN-1 and its prodrug, molsidomine. PRG150 produced dose-dependent analgesia in STZ-diabetic rats whereas SIN-1 and molsidomine evoked neuro-excitatory side-effects, but not analgesia. The 1000-fold larger doses of PRG150 needed to produce analgesia at 14- and 24-weeks (800pmol/kg) c.f. 10-weeks (8fmol/kg) post-STZ in rats, suggest that progressive NO depletion is also causal in PDN. Importantly, doses of PRG150 up to 10000 fold higher than the analgesic dose did not produce hypotension in rats. The 50-fold greater release of NO by SIN-1 c.f. PRG150 invitro, may underpin the neuro-excitatory rather than analgesic effects of SIN-1/molsidomine. PRG150 is worthy of further investigation as a potential novel analgesic for PDN.

The role of arginine vasopressin in electroacupuncture treatment of primary sciatica in human

It has been implicated that electroacupuncture can relieve the symptoms of sciatica with the increase of pain threshold in human, and arginine vasopressin (AVP) in the brain rather than the spinal cord and blood circulation participates in antinociception. Our previous study has proven that AVP in the brain played a role in the process of electroacupuncture analgesia in rat. The goal of the present study was to investigate the role of AVP in electroacupuncture in treating primary sciatica in human. The results showed that (1) AVP concentration of cerebrospinal fluid (CSF) (7.5±2.5pg/ml), not plasma (13.2±4.2pg/ml) in primary sciatica patients was lower than that in health volunteers (16.1±3.8pg/ml and 12.3±3.4pg/ml), although the osmotic pressure in CSF and plasma did not change; (2) electroacupuncture of the bilateral “Zusanli” points (St. 36) for 60min relieved the pain sensation in primary sciatica patients; (3) electroacupuncture increased the AVP level of CSF, not plasma in primary sciatica patients; and (4) there was the positive correlation between the effect of electroacupuncture relieving the pain and the AVP level of CSF in the primary sciatica patients. The data suggested that central AVP, not peripheral AVP might improve the effect of electroacupuncture treatment of primary sciatica in human, i.e., central AVP might take part in the electroacupuncture relieving the pain sensation in primary sciatica patients.

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

The purpose of the experiment was to assess interactions of dopamine with propranolol as an infiltrative anesthetic. After 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. We 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. The 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 propranolol's cutaneous analgesic effect.

μ-Opioid and N-methyl-D-aspartate receptors in the amygdala contribute to minocycline-induced potentiation of morphine analgesia in rats.

The aim of the present study was to investigate the role of the amygdala in the potentiative effect of minocycline, a semisynthetic tetracycline antibiotic, on morphine analgesia in male Wistar rats. We also examined the involvement of the amygdala μ-opioid and N-methyl-D-aspartate (NMDA) receptors in the minocycline-induced potentiation of morphine analgesia. Intraperitoneal administration of morphine (3-9 mg/kg) induced analgesia in a tail-flick test. Bilateral intra-amygdala injection of minocycline (10-20 μg/rat) enhanced the analgesic response of an ineffective dose of morphine (3 mg/kg). Injection of a higher dose of minocycline into the amygdala also induced analgesia. Moreover, bilateral intra-amygdala injection of naloxone (0.5-1.5 µg/rat) reversed minocycline-induced potentiation of morphine analgesia. Pretreatment of animals with NMDA (0.01-0.1 μg/rat, intra-amygdala) also inhibited the potentiative effect of minocycline on morphine response. Bilateral intra-amygdala injection of the same doses of naloxone or NMDA plus morphine had no effect on the tail-flick latency in the absence of minocycline. It can be concluded that the amygdala has a key role in the potentiative effect of minocycline on morphine analgesia. In addition, amygdala opioidergic and glutamatergic mechanisms may be involved, probably through μ-opioid and NMDA receptors, in the modulation of the minocycline-induced potentiation of morphine analgesia in the tail-flick test.