Synergistic interaction between intrathecal ginsenosides and morphine on formalin-induced nociception in rats.

UNLABELLED: We defined the nature of the pharmacological interaction between ginsenosides and morphine in a nociceptive state and clarified the role of the different types of opioid receptor in the effects of ginsenosides. An intrathecal catheter was placed in male Sprague-Dawley rats. Pain was induced by formalin injection into the hindpaw. Isobolographic analysis was used to evaluate drug interactions. Furthermore, a nonselective opioid receptor antagonist (naloxone), a µ opioid receptor antagonist (CTOP), a δ opioid receptor antagonist (naltrindole), and a κ opioid receptor antagonist (GNTI) were given intrathecally to verify the involvement of the opioid receptors in the antinociceptive effects of ginsenosides. Both ginsenosides and morphine produced antinociceptive effects in the formalin test. Isobolographic analysis revealed a synergistic interaction after intrathecal delivery of the ginsenosides-morphine mix. Intrathecal CTOP, naltrindole, and GNTI reversed the antinociceptive effects of ginsenosides. RT-PCR indicated that opioid receptors' mRNA was detected in spinal cord of naïve rats and the injection of formalin had no effect on the expression of opioid receptors' mRNA. Taken together, our results indicate synergistic antinociception following intrathecal coadministration of a ginsenosides/morphine mix in the formalin test, and that µ, δ, and κ opioid receptors are involved in the antinociceptive mechanism of ginsenosides. PERSPECTIVE: This article concerns the antinociceptive activity of ginsenosides, which increases antinociception by morphine. Thus, a spinal combination of ginsenosides and morphine may be useful in the management of acute pain as well as facilitated state pain.

Antinociceptive effect of intrathecal cannabinoid receptor agonist WIN 55,212-2 in a rat bone tumor pain model.

Bone tumor pain is a poorly controlled pain comprising background and severe pain on moving or weight-bearing postures that decreases the quality of life for cancer patients; thus, more effective analgesics are clearly needed. This study evaluated the efficacy of a cannabinoid (CB) receptor agonist (WIN 55,212-2) on bone tumor pain in the spinal cords of rats, and clarified the roles of the CB1 and CB2 receptors in WIN 55,212-2-induced antinociception at the spinal level. Bone tumor pain was induced by injecting MRMT-1 tumor cells (1×10(5)) into the right tibias of female Sprague-Dawley rats under sevoflurane anesthesia. Bone tumor development was monitored radiologically. Under sevoflurane anesthesia, a polyethylene catheter was inserted into the intrathecal space for drug administration. To assess pain, the withdrawal threshold was measured by applying a von Frey filament to the tumor cell inoculation site. The effect of intrathecal WIN 55,212-2 was investigated. Next, the WIN 55,212-2-mediated antinociception was reversed using CB1 (AM 251) and CB2 (AM 630) receptor antagonists. The intratibial injection of MRMT-1 tumor cells produced radiologically confirmed bone tumors. The paw withdrawal threshold decreased significantly (mechanical allodynia) with tumor development; however, intrathecal WIN 55,212-2 dose-dependently increased the withdrawal threshold. The antinociceptive effect of WIN 55,212-2 was reversed by both CB1 and CB2 receptor antagonists. Intrathecal WIN 55,212-2 reduced bone tumor-related pain behavior mediated via spinal CB1 and CB2 receptors. Therefore, spinal CB receptor agonists may be novel analgesics in the treatment of bone tumor pain.

A randomized controlled trial of intra-articular prolotherapy versus steroid injection for sacroiliac joint pain.

OBJECTIVES: Controversy exists regarding the efficacy of ligament prolotherapy in alleviating sacroiliac joint pain. The inconsistent success rates reported in previous studies may be attributed to variability in patient selection and techniques between studies. It was hypothesized that intra-articular prolotherapy for patients with a positive response to diagnostic block may mitigate the drawbacks of ligament prolotherapy. The purpose of this study was to evaluate the efficacy and long-term effectiveness of intra-articular prolotherapy in relieving sacroiliac joint pain, compared with intra-articular steroid injection. DESIGN: This was a prospective, randomized, controlled trial. SETTINGS/LOCATION: The study was conducted at an outpatient pain medicine clinic at Chonnam National University Hospital in Gwang-ju, Korea. SUBJECTS: The study included patients with sacroiliac joint pain, confirmed by ≥50% improvement in response to local anesthetic block, lasting 3 months or longer, and who failed medical treatment. INTERVENTIONS: The treatment involved intra-articular dextrose water prolotherapy or triamcinolone acetonide injection using fluoroscopic guidance, with a biweekly schedule and maximum of three injections. OUTCOME MEASURES: Pain and disability scores were assessed at baseline, 2 weeks, and monthly after completion of treatment. RESULTS: The numbers of recruited patients were 23 and 25 for the prolotherapy and steroid groups, respectively. The pain and disability scores were significantly improved from baseline in both groups at the 2-week follow-up, with no significant difference between them. The cumulative incidence of ≥50% pain relief at 15 months was 58.7% (95% confidence interval [CI] 37.9%-79.5%) in the prolotherapy group and 10.2% (95% CI 6.7%-27.1%) in the steroid group, as determined by Kaplan-Meier analysis; there was a statistically significant difference between the groups (log-rank p < 0.005). CONCLUSIONS: Intra-articular prolotherapy provided significant relief of sacroiliac joint pain, and its effects lasted longer than those of steroid injections. Further studies are needed to confirm the safety of the procedure and to validate an appropriate injection protocol.

Roles of opioid receptor subtype in the spinal antinociception of selective cyclooxygenase 2 inhibitor.

BACKGROUND: Selective inhibitors of cyclooxygenase (COX)-2 are commonly used analgesics in various pain conditions. Although their actions are largely thought to be mediated by the blockade of prostaglandin (PG) biosynthesis, evidences suggesting endogenous opioid peptide link in spinal antinociception of COX inhibitor have been reported. We investigated the roles of opioid receptor subtypes in the spinal antinociception of selective COX-2 inhibitor. METHODS: To examine the antinociception of a selective COX-2 inhibitor, DUP-697 was delivered through an intrathecal catheter, 10 minutes before the formalin test in male Sprague-Dawley rats. Then, the effect of intrathecal pretreatment with CTOP, naltrindole and GNTI, which are µ, δ and κ opioid receptor antagonist, respectively, on the analgesia induced by DUP-697 was assessed. RESULTS: Intrathecal DUP-697 reduced the flinching response evoked by formalin injection during phase 1 and 2. Naltrindole and GNTI attenuated the antinociceptive effect of intrathecal DUP-697 during both phases of the formalin test. CTOP reversed the antinociception of DUP-697 during phase 2, but not during phase 1. CONCLUSIONS: Intrathecal DUP-697, a selective COX-2 inhibitor, effectively relieved inflammatory pain in rats. The δ and κ opioid receptors are involved in the activity of COX-2 inhibitor on the facilitated state as well as acute pain at the spinal level, whereas the µ opioid receptor is related only to facilitated pain.

Synergistic antinociception of intrathecal sildenafil with clonidine in the rat formalin test.

Spinal sildenafil (phosphodiesterase 5 inhibitor) and clonidine (alpha-2 adrenoceptor agonist) have shown antinociception. The author examined the properties of drug interaction after concurrent administration of intrathecal sildenafil-clonidine, and further clarified the reciprocity of sildenafil and clonidine. Catheters were inserted into the intrathecal space of male Sprague-Dawley rats. The formalin test was used as a nociceptive test, which was induced by subcutaneous injection of 50 microl of 5% formalin solution into the hindpaw. The pharmacological interaction was characterized using an isobolographic analysis. Intrathecal sildenafil and clonidine dose-dependently suppressed the flinching response observed during phase 1 and phase 2 in the formalin test. Isobolographic analysis revealed a synergistic interaction after intrathecal delivery of sildenafil-clonidine in both phases. Intrathecal yohimbine antagonized the antinociceptive action of intrathecal sildenafil during both phases in the formalin test. However, intrathecal ODQ failed to antagonize the antinociceptive action of intrathecal clonidine. These results suggest that sildenafil and clonidine, and the mixture of the two are effective against acute pain and facilitated pain state at the spinal level. Furthermore, synergism was noted after delivery of sildenafil-clonidine mixture. The antinociception of sildenafil can be modulated by spinal alpha-2 adrenoceptor, while the effect of clonidine is independent on the guanyly cyclase.

Lack of reciprocity between opioid and 5-HT3 receptors for antinociception in rat spinal cord.

We examined the properties of the drug interaction between morphine and 5-HT(3) receptor antagonist at the spinal level. The nociceptive state was induced by subcutaneously injecting formalin solution (5%, 50 microl) into the hindpaw of the rats. Intrathecal morphine and m-CPBG (5-HT(3) receptor agonist) dose-dependently decreased the flinching response during phase 1 and phase 2 in the formalin test. Intrathecal 5-HT(3) receptor antagonists (LY-278,584 and ondansetron) did not reverse the antinociceptive effect of intrathecal morphine. Intrathecal naloxone had little effect on attenuation of the antinociception of intrathecal m-CPBG. Taken together, no reciprocal interaction was noted between 5-HT(3) receptor and opioid receptors at the spinal level. Thus, the 5-HT(3) receptor antagonist may be useful to manage opioid-induced emesis at the spinal level.

Roles of adenosine receptor subtypes in the antinociceptive effect of intrathecal adenosine in a rat formalin test.

The contributions of adenosine receptor subtypes to antinociception produced by adenosine were determined at the spinal level. There are 4 types of adenosine receptors, namely A1, A(2A), A(2B) and A3. The authors investigated the properties of the subtypes of spinal adenosine receptors in terms of nociceptive modulation. The nociceptive state was induced by subcutaneously injecting formalin solution (5%, 50 microl) into the hind paws of male Sprague-Dawley rats. After observing the effect of intrathecal adenosine during the formalin test, the effects of intrathecal adenosine A1 (CPT), A(2A) (CSC), A(2B) (alloxazine) and A3 (MRS 1220) receptor antagonists on the action of adenosine were examined. Intrathecal adenosine inhibited phase 2 flinching response without affecting phase 1 response. CPT, CSC, alloxazine and MRS 1220 antagonized the antinociceptive action of adenosine during phase 2 of the formalin test. These results suggest that spinal adenosine A1, A(2A), A(2B) and A3 receptors may play an important role in the antinociception of adenosine in the formalin-induced facilitated state.

Evaluation of interaction between intrathecal adenosine and MK801 or NBQX in a rat formalin pain model.

Adenosine and excitatory amino acids have been known to be involved in modulating nociceptive transmission at the spinal level. The authors assessed the characteristics of the interaction of the adenosine-excitatory amino acid antagonist combinations in the spinal cord of rats on the formalin-induced nociception. Intrathecal NMDA antagonist ((5R, 10S)-(+)-5-methyl-10,11-dihydro-(5)H-dibenzo[a[,]d]cyclohepten-5,10-imine hydrogen maleate, MK801, 30 microg) and AMPA antagonist (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[F]quinoxaline-7-sulfonamide, NBQX, 3 microg) decreased the total number of flinches during both phases in the formalin test. Intrathecal adenosine (300 microg) had little effect on the phase 1 flinching response, but decreased the phase 2 response. The fixed dose analysis and the isobolographic analysis revealed that adenosine interacts additively with MK801 and NBQX in the spinal cord.

Lack of the nitric oxide-cyclic GMP-potassium channel pathway for the antinociceptive effect of intrathecal zaprinast in a rat formalin test.

Zaprinast is a phosphodiesterase inhibitor that is active in various models of pain when administered locally. In addition, the antinociception of zaprinast is involved in the nitric oxide (NO)-cGMP pathway. However, the effect of zaprinast administered spinally has not been examined. Therefore, this study examined the effect of zaprinast on the formalin-induced nociception at the spinal level. Next, the role of the NO-cGMP-potassium channel pathway on the effect of zaprinast was further clarified. Catheters were inserted into the intrathecal space of male Sprague-Dawley (SD) rats. Pain was induced by applying 50 microl of a 5% formalin solution to the hindpaw. The change in the zaprinast-induced effect was examined after an intrathecal pretreatment with a NO synthase inhibitor (l-NMMA), a guanylyl cyclase inhibitor (ODQ) or a potassium channel blocker (glibenclamide). Zaprinast produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. Intrathecal l-NMMA, ODQ and glibenclamide did not reverse the antinociception of zaprinast in either phase of the formalin test. These results suggest that zaprinast is effective against both acute pain and the facilitated pain state at the spinal level. However, the NO-sensitive cGMP-potassium channel pathway is not contributable to the antinociceptive mechanism of zaprinast in the spinal cord.