Non-opioid Mechanisms Research Articles

Extended-release formulations of tramadol in the treatment of chronic pain

Introduction: Tramadol is a centrally acting analgesic available throughout the world. Its dual opioid and non-opioid mechanisms of action, favorable efficacy and safety clinical profiles and non-controlled regulatory status in most markets contribute to its widespread use. A drawback of the immediate-release formulation of tramadol (four-times-a-day dosing) might be addressed by an extended-release formulation. Extended-release formulations also can offer advantages in the management of chronic pain: convenience, reduced pill burden (possibly leading to improved compliance) and the attenuation of peaks and troughs in serum concentration (possibly leading to reduced adverse effects).Areas covered: The authors review tramadol's mechanisms of action and the clinical literature regarding the use of tramadol extended-release formulations for the management of conditions involving chronic pain, such as neuropathic pain syndromes, osteoarthritis and cancer pain.Expert opinion: Based on the literature cited, extended-release formulations of tramadol seem to offer a rational and important addition to the analgesic armamentarium. As is true for all such options, the benefits and risks must be assessed for each patient.

Abstract 4526: Inhibition of human multiple myeloma proliferation by naltrindole

Abstract The purpose of this study was to test and characterize the antiproliferative activity of naltrindole (Nti), a selective delta opioid receptor antagonist, toward human multiple myeloma (MM) cells. Nti has been shown to inhibit the allogeneic mixed lymphocyte reaction in vitro, and to block graft rejection in vivo, similarly to cyclosporine A. Based on its immunosuppressive properties we decided to test the effects of Nti on proliferation of MM cells. MM is an invasive and incurable plasma cell neoplasm responsible for 10% of all hematological malignancies. We have screened a variety of opioid compounds for activity against MM and we found that Nti inhibited the proliferation of several human MM cell lines (U266, RPMI 8226, ARP1) with an EC50 of approximately 20 μM, whereas a variety of other human cells lines were substantially less sensitive. Co-culture of MM cells with human bone marrow stromal cells did not affect the antiproliferative activity of Nti. A 10-fold molar excess of naltrexone, a non-selective opioid antagonist, did not block the Nti-induced inhibition of U266 cell proliferation. [3H]-Nti exhibits saturable, low affinity binding to intact MM cells and the pharmacological properties of the Nti binding site differ significantly from the properties of the delta opioid receptor, leading us to hypothesize that Nti inhibits proliferation of MM cells through a non-opioid receptor-dependent mechanism. RT-PCR assays confirmed the lack of delta, kappa and mu receptor mRNA in U266 and RPMI 8226 MM cells. The identity of the naltrindole binding site is currently under investigation. Nti does not induce apoptosis in MM cells, based on FACS analysis and caspase cleavage assays. While investigating the mechanism of action of Nti, we have observed that it increases intracellular calcium levels in MM cells, and the calcium appears to be released from the endoplasmic reticulum, based on inhibition of the response following thapsigargin treatment. This effect is specific to Nti as other opioids such as naltrexone and morphine do not affect the levels of calcium in MM cells, nor do they block the activity of Nti. Based on the observed in vitro anti-proliferative activity of Nti toward MM cell lines, an in vivo study was conducted. Nti injected IP daily at 30mg/kg significantly decreased tumor volumes in a murine SCID/human RPMI 8226 xenograft model over a 39-day period compared with saline injected controls. Curcumin, a constituent of turmeric extracted from the rhizomes of the plant Curcuma longa) has been shown to induce apoptosis in MM cells. We have also observed that curcumin inhibits the proliferation of MM cells. Although the chemical structures of Nti and curcumin differ substantially, curcumin inhibits Nti binding with an EC50 of 58 µM in MM cells. It appears that Nti and curcumin warrant further study as potential therapeutic agents for the treatment of human MM. Supported by grants from NIDA, the NJ Commission on Cancer Research, and the Foundation of UMDNJ. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4526. doi:10.1158/1538-7445.AM2011-4526

P.4.001 Influence of single and chronic intranasal injections of the arginine-vasopressin fragment Ac-D-MPRG on the ontogeny of the behavioural reactions in white rats

KAVALIERS, M., E. CHOLERIS AND D. M. SAUCIER.The NMDA receptor antagonist, NPC 12626, reduces the pronociceptive effects of orphanin FQ, and kappa opiate antinociception in the land snail, Cepaea nemoralis. PEPTIDES 18(7) 943–947, 1997.—The heptadecapeptide, orphanin FQ or nociceptin (Phe-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln), originally isolated from rat brain has been identified as an endogenous ligand for the orphan opioid-like receptor. Although orphanin FQ shares some sequence and structural homology with kappa-opioid peptides, it has been speculated to exert its effects through novel nonopioid mechanisms. Kappa opioids have also been suggested to have nonopioid actions in rodents involving the N-methyl-D-aspartate (NMDA) receptor. The present study examined the effects of the competitive NMDA antagonist, NPC 12626, on the antinociceptive effects of the specific kappa-opiate receptor agonist, U69,593, and the pronociceptive effects of orphanin FQ in an invertebrate system, the land snail, Cepaea nemoralis. NPC 12626 had no effect on the basal nociceptive sensitivity of snails, as measured by the latency of response to a thermal (40°C) surface. As reported for rodents, NPC 12626 dose-dependently reduced U69,593-induced antinociception in a manner comparable to that produced by the specific kappa-opiate antagonist, nor-binaltorphimine, while slightly enhancing the antinociceptive effects of the predominately mu-opiate agonist, morphine. Similarly, NPC 12626 dose-dependently reduced the pronociceptive effects of orphanin FQ. These findings with the snail, Cepaea, indicate that NMDA systems/receptors are associated with the mediation of the nociceptive effects of both kappa opioids and orphanin FQ. They suggest an early evolutionary development and phylogenetic continuity of NMDA opioid and related neuropeptide interactions in the mediation of nociception.

The nitric oxide–cGMP signaling pathway plays a significant role in tolerance to the analgesic effect of morphine

Although the phenomenon of opioid tolerance has been widely investigated, neither opioid nor nonopioid mechanisms are completely understood. The aim of the present study was to investigate the role of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway in the development of morphine-induced analgesia tolerance. The study was carried out on male Wistar albino rats (weighing 180-210 g; n = 126). To develop morphine tolerance, animals were given morphine (50 mg/kg; s.c.) once daily for 3 days. After the last dose of morphine was injected on day 4, morphine tolerance was evaluated. The analgesic effects of 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), BAY 41-2272, S-nitroso-N-acetylpenicillamine (SNAP), N(G)-nitro-L-arginine methyl ester (L-NAME), and morphine were considered at 15 or 30 min intervals (0, 15, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests (n = 6 in each study group). The results showed that YC-1 and BAY 41-2272, a NO-independent activator of soluble guanylate cyclase (sGC), significantly increased the development and expression of morphine tolerance, and L-NAME, a NO synthase (NOS) inhibitor, significantly decreased the development of morphine tolerance. In conclusion, these data demonstrate that the nitric oxide-cGMP signal pathway plays a pivotal role in developing tolerance to the analgesic effect of morphine.

Drug profile: tramadol for moderate to severe pain

Tramadol, while classified as an opioid analgesic, works through a combination of both opioid and non-opioid mechanisms. It is an effective analgesic in the management of visceral moderate to severe pain, and is ideal for use in the minor injuries setting. This article will consider the pharmacological basis of tramadol and how it works by giving an overview of the physiology of pain and neurotransmitters. Discussion will focus on the safe prescribing of tramadol in clinical practice, including the vulnerable patient groups requiring extra consideration, potential drug interactions and how to avoid complications when prescribing this drug. Finally, by outlining the prescribing pyramid, it is demonstrated how safe practice is guided in the clinical setting.

Electroacupuncture on Visceral Hyperalgesia - What Is Its Mechanism?

Electroacupuncture on Visceral Hyperalgesia - What Is Its Mechanism?

Antinociceptive and Antiedematogenic Activities of Andrographolide Isolated From Andrographis paniculata in Animal Models

The current study was performed to evaluate the antinociceptive and antiedematogenic properties of andrographolide isolated from the leaves of Andrographis paniculata using two animal models. Antinociceptive activity was evaluated using the acetic acid- induced writhing and the hot-plate tests, while antiedematogenic activity was measured using the carrageenan-induced paw edema test. Subcutaneous (s.c.) administration of andrographolide (10, 25, and 50 mg/kg) did not affect the motor coordination of the experimental animals but produced significant (p < .05) antinociceptive activity when assessed using both tests. However, 2 mg/kg naloxone failed to affect the 25 mg/kg andrographolide activity in both tests, indicating that the activity was modulated via nonopioid mechanisms. Furthermore, andrographolide showed significant (p < .05) antiedematogenic activity. In conclusion, the results obtained suggest that andrographolide has antinociceptive and antiedematogenic activities; it may be useful for treating pain and inflammation once human studies are conducted.

Comparative studies of the neuro-excitatory behavioural effects of morphine-3-glucuronide and dynorphin A(2-17) following spinal and supraspinal routes of administration

Morphine-3-glucuronide (M3G) administered centrally produces dose-dependent neuro-excitatory behaviours in rodents via a predominantly non-opioid mechanism. The endogenous opioid peptide, dynorphin A (Dyn A) (1-17), is rapidly cleaved in vivo to the relatively more stable fragment Dyn A(2-17) which also produces excitatory behaviours in rodents via a non-opioid mechanism. This study investigated the possible contribution of Dyn A(2-17) to the neuro-excitatory behaviours evoked by supraspinally and spinally administered M3G in male Sprague–Dawley (SD) rats. Marked qualitative differences in behaviours were apparent following administration of M3G and Dyn A(2-17). Administration of 11 nmol i.c.v. doses of M3G produced intermittent myoclonic jerks, tonic–clonic convulsions, and ataxia, as well as postural changes, whereas i.c.v. Dyn A(2-17) at 15 nmol produced effects on body posture alone. Administration of 11 nmol i.t. doses of M3G produced intermittent explosive motor activity, and touch-evoked agitation, as well as postural changes, whereas i.t. Dyn A(2-17) at 15 nmol produced postural changes, touch-evoked agitation, and paralysis. Pre-treatment with Dyn A antiserum (200 µg) markedly attenuated total behavioural excitation following i.c.v. and i.t. administration of Dyn A(2-17) by ∼ 94% and 78%, respectively. However, total behavioural excitation following i.c.v. and i.t. administration of M3G was less markedly attenuated (both ∼ 27%) by pre-treatment with Dyn A antiserum, with reductions in tonic–clonic convulsions (∼ 43%), explosive motor behaviour (∼ 28%), and touch-evoked agitation (∼ 22%). The present findings discount a major role for Dyn A in mediating the neuro-excitatory effects of M3G, although it may contribute to maintaining some individual neuro-excitatory behaviours.

Hibernation-like state induced by an opioid peptide protects against experimental stroke

BackgroundDelta opioid peptide [D-ala2,D-leU5]enkephalin (DADLE) induces hibernation in summer ground squirrels, and enhances preservation and survival of isolated or transplanted lungs and hearts. In the present study, we investigated the protective effect of DADLE in the central nervous system.ResultsAdult Sprague-Dawley rats were pretreated with DADLE (4 mg/kg every 2 h × 4 injections, i.p.) or saline prior to unilateral occlusion of the middle cerebral artery (MCA). Daily behavioral tests revealed that ischemic animals treated with DADLE did not show any significant behavioral dysfunctions compared with saline-treated ischemic animals. Opioid antagonists only transiently inhibited the protective effect of DADLE, indicating the participation of non-opioid mechanisms in DADLE neuroprotection. Histological examination using triphenyltetrazolium chloride (TTC) revealed that brains from ischemic animals treated with DADLE, either alone or with adjuvant opioid blockers, exhibited almost completely intact striata. In contrast, brains from ischemic animals that received saline showed significant infarction in the lateral striatum. Analyses of apoptotic cell death revealed a significant increase in the p-53 mRNA expression in the striatum of ischemic animals that received saline, while those that received DADLE exhibited near normal striatal p-53 expression. This protective effect was accompanied by significant increments in protein levels of glial cell line-derived neurotrophic factor in the striatum of DADLE-treated ischemic animals.ConclusionThese results indicate that DADLE protected against necrotic and apoptotic cell death processes associated with ischemia-reperfusion injury. The present study demonstrates that delta opioids are crucially involved in stroke, suggesting that the opioid system is important in the study of brain injury and protection.

Dissection of placebo analgesia in mice: the conditions for activation of opioid and non-opioid systems

Amanzio and Benedetti (J Neurosci 1999; 19: 484-494) first addressed the conditions necessary for the activation of opioid and non-opioid placebo responses in human. Here, we investigated whether placebo analgesia is subdivided into opioid and non-opioid components in mice by using the model of hot-plate test. Drug conditioning was performed by the combination of the conditioned cue stimulus with the unconditioned drug stimulus, either opioid agonist morphine hydrochloride or non-opioid aspirin. Placebo analgesic responses were evoked by an exposure to a conditioned cue previously paired with drug conditioning. Morphine conditioning produced placebo responses that were completely antagonised by naloxone. By contrast, the conditioned cue after aspirin conditioning elicited a placebo effect that was not blocked by naloxone. Therefore, we first evoked opioid and non-opioid placebo responses in mice that were either naloxone-reversible or naloxone-insensitive, depending on the drug used in conditioning procedure. These findings support that the mechanisms underlying placebo analgesia may depend on the drug conditioning that was originally performed. The present procedure of mice may serve as a model for further understanding of the opioid and non-opioid mechanisms underlying placebo responses.

Tramadol-induced block of hyperpolarization-activated cation current in rat pituitary lactotrophs

The hyperpolarization-activated cation current (I (h)) in rat pituitary lactotrophs (GH(3) cells) was characterized. Tramadol-induced block of this current was investigated. Effects of various related compounds on I (h) in GH(3) cells were also compared. Tramadol caused a time- and concentration-dependent reduction in the amplitude of I (h) with an IC(50) value of 13.6 microM. ZD7288 (30 microM), CsCl (2 mM), and propofol (30 microM) were effective in suppressing the amplitude of I (h). 2',5'-dideoxyadenosine (100 microM) suppressed I (h), while sp-cAMPS (100 microM) had no effect on it. Tramadol (10 microM) shifted the activation curve of I (h) to a more negative potential by approximately -20 mV, although no change in the slope factor was observed. Under current-clamp configuration, tramadol (10 microM) could reduce the firing frequency of action potentials. Intracellular Ca(2+) measurements revealed its ability to reduce spontaneous Ca(2+) oscillations in GH(3) cells. The results suggests that during cell exposure to tramadol used at clinically relevant concentration, the tramadol-mediated inhibition of I (h) could be direct and mediated via a non-opioid mechanism and would be one of the ionic mechanisms underlying reduced cell excitability.

The role of hypothalamo-hypophyseal-adrenocortical system hormones in controlling pain sensitivity

The present review addresses analysis of data demonstrating the role of the hypothalamo-hypophyseal-adrenocortical axis (HHACA) in controlling pain sensitivity. Experiments on rats have demonstrated the analgesic effects of exogenous hormones of all components of the HHACA - corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and glucocorticoids - in the same models, and have also shown that the opioid and non-opioid mechanisms contribute to the development of the analgesia induced by these hormones. Endogenous glucocorticoids are involved in the development of analgesia mediated by non-opioid mechanisms. Along with the non-opioid mechanisms associated with endogenous glucocorticoids, the analgesic effect of ACTH can be mediated by the opioid mechanism. Unlike the situation with ACTH, the analgesic effect of CRH is mediated exclusively by non-opioid mechanisms, one of which is associated with HHACA hormones, while the other, appearing only on systemic administration, is not associated with these hormones. The actions of glucocorticoids on pain are mediated by neurons in the central gray matter of the midbrain.

Evaluation of antinociceptive and antiinflammatory effects of Croton pullei var. glabrior Lanj. (Euphorbiaceae)

Croton pullei var. glabrior Lanj. (Euphorbiaceae) is a liana, vastly distributed in the Amazonian Forest. In the folk medicine, several plants of the Croton genus have been used with therapeutic purposes in pathologies that involve painful and inflammatory diseases which justify this work. The aim of this study was to investigate the antinociceptive and antiinflammatory activities of the C. pullei leaves methanol extract (MECP). MECP reduced in a dose-dependent manner the number of acetic acid-induced abdominal writhing (1.2%) in mice, suggesting an antinociceptive activity of the plant. On the other hand, MECP did not significantly modify the reactivity to the thermal stimulation in the hot-plate test and the reactivity to the chemical stimulation in the formalin test first phase, indicating a non-opioid mechanism. MECP reduced the formalin-induced nociception in the second phase, inhibited the croton oil-induced ear edema and reduced the leukocytes migration in the test of the carrageenan-induced peritonitis, indicating an antiinflammatory activity. Although the mechanisms that underlie these plant effects are not completely elucidated, these results appear to support the potential medicinal use of Croton pullei var. glabrior Lanj. against painful and inflammatory diseases.

Sex differences in opioid-mediated pain inhibitory mechanisms during the interphase in the formalin test

Many chronic pain conditions are more prevalent in women than men and both fundamental and clinical research supports the implication of endogenous pain inhibitory mechanisms. The goal of this study was to verify if sex differences on endogenous pain inhibitory mechanisms during the formalin test are opioidergic and modulated by sex hormones. Formalin tests were performed with naloxone hydrochloride, a non-selective opioid antagonist in intact and gonadectomized Sprague–Dawley rats of both sexes. Considering the sexual dimorphisms we found, where naloxone preferentially blocked the interphase in female rats, injections of all the possible combinations of μ- (naltrexone hydrochloride), δ- (naltrindole hydrochloride) and κ-selective antagonists (norbinaltorphimine dihydrochloride) were given to evaluate the contribution of these opioid-receptor subtypes to the inhibitory mechanism during the interphase in intact females. Finally, the systemic administration of naloxone methiodide and intrathecal administration of naloxone hydrochloride in intact females allowed us to verify if the action of endogenous opioids that are liberated during the interphase takes place at the periphery or spinally, respectively. The results show that the interphase was almost completely inhibited by naloxone in females while it produced only a slight blockade in males. These results permitted us to conclude that opioids play a major role in the pain inhibitory mechanism of the interphase in females while a non-opioid mechanism seems to be responsible for this inhibitory pathway in males. Using gonadectomized animals of both sexes, we demonstrated the modulation of the opioidergic system of the interphase by sex hormones. The administration of different combinations of selective antagonists for μ-, κ- and δ-opioid receptors in intact females permitted us to conclude that only the combination of κ- and δ-selective antagonists significantly blocked the interphase. The same result was obtained with the combination of the three antagonists, confirming the results with systemic naloxone hydrochloride. Finally, intrathecal administration permitted us to support that the action of naloxone is primarily at the spinal level, even if a supraspinal action cannot be ruled out. These results are of particular interest in showing sexual dimorphisms in endogenous pain modulation mechanisms during the interphase of the formalin test. A clearer understanding of the difference between male and female endogenous pain inhibitory pathways should lead to a better understanding of the role of endogenous pain modulation deficits in certain chronic pain conditions.

Dynorphin displaces binding at the glycine site of the NMDA receptor in the rat striatum

Binding of dynorphin A (1–17 and 2–17) to NMDA receptors in the rat striatum was studied by displacing radioactive ligands for the receptor's polyamine ([ 3H]-Ifenprodil), glutamate ([ 3H]-CGP-39653), dizocilpine ([ 3H]-MK-801) and glycine ([ 3H]-MDL105,519) sites with the neuropeptide. Dynorphin A selectively displaced [ 3H]-MDL105,519 and none of the other ligands. Opioid antagonists did not affect displacement. Thus, in the striatum dynorphin may regulate NMDA receptor function via the glycine B site through non-opioid mechanisms. This may contribute to the long-term changes in behavioral responsiveness seen after dopamine depletion and treatment with dopaminomimetics which are associated with substantial changes in striatal dynorphin metabolism.

Dextro‐Naloxone or levo‐naloxone reverses the attenuation of morphine antinociception induced by lipopolysaccharide in the mouse spinal cord via a non‐opioid mechanism

Glial stimulation by intrathecal injection of lipopolysaccharide (LPS) attenuated the tail-flick inhibition produced by morphine given intrathecally in the spinal cord of the male CD-1 mice. The phenomenon has been defined as antianalgesia. The effects of dextro-naloxone or levo-naloxone on the attenuation of morphine-produced tail-flick inhibition induced by LPS were then studied. Pretreatment with dextro-naloxone or levo-naloxone reversed the attenuation of the morphine-produced tail-flick inhibition induced by LPS. Pretreatment with dextro-naloxone or levo-naloxone alone did not affect the morphine-produced tail-flick inhibition. It is concluded that dextro-naloxone and levo-naloxone block the LPS-induced antianalgesia against morphine antinociception via a non-opioid mechanism.

Mechanisms of acupuncture analgesia for clinical and experimental pain

There is convincing evidence that acupuncture (AP) is effective for the treatment of postoperative and chemotherapy-induced nausea/vomiting, as well as postoperative dental pain. Less convincing data support AP’s efficacy for chronic pain conditions, including headache, fibromyalgia and low back pain. There is no evidence that AP is effective in treating addiction, insomnia, obesity, asthma or stroke deficits. AP seems to be efficacious for alleviating experimental pain by increasing pain thresholds in human subjects and it appears to activate analgesic brain mechanisms through the release of neurohumoral factors, some of which can be inhibited by the opioid antagonist naloxone. In contrast to placebo analgesia, AP-related pain relief takes some time to develop and to resolve. Furthermore, repetitive use of AP analgesia can result in tolerance that demonstrates cross-tolerance with morphine. However, it appears that not all forms of AP are equally effective for providing analgesia. In particular, electro-AP seems to best deliver stimuli that activate powerful opioid and nonopioid analgesic mechanisms. Thus, future carefully controlled clinical trials using adequate electro-AP may be able to provide the necessary evidence for relevant analgesia in chronic pain conditions, such as headache, fibromyalgia, irritable bowel syndrome and low back pain.

Methadone for Persistent Pain in the Older Patient

Methadone is a synthetic opioid analgesic developed almost 60 years ago in response to a shortage of supplies of traditional opioids caused by the Second World War. Until a few years ago, this agent saw relatively little use other than as a maintenance therapy in narcotic addicts. A lack of knowledge regarding the unusual pharmacokinetics and pharmacodynamics of the drug and their impact on its clinical use invited therapeutic misadventures, which manifested as delayed severe toxicity. With the discovery and dissemination of the pharmacokinetic and pharmacodynamic behaviors and nonopioid mechanisms of action of methadone over the past 10–15 years, support for the use of methadone as a first-line opioid analgesic has been slowly progressing. Risk factors for excessive methadone accumulation have been identified, as have several dosing methodologies that allow its safe use, even in the oldest individuals. Methadone is no longer a medication only to be used by specialists in pain clinics. However, it should be used only by clinicians who are experienced in the use and monitoring of opioids, especially when moderate or high doses are required. This review summarizes the information necessary to allow its safe and effective use in the elderly population.

Effects of Prolonged Treatment With the Opiate Tramadol on Prodynorphin Gene Expression in Rat CNS

A low abuse liability is reported for tramadol, an analgesic drug centrally acting through either opioid or nonopioid mechanisms. In this paper, we evaluated the effects of the repeated administration (7 d) of different doses of tramadol (10, 20, and 80 mg/kg, intraperitoneally) on the opioid precursor prodynorphin biosynthesis, in comparison with morphine (10 mg/kg, intraperitoneally), in the rat central nervous system (CNS). Northern analysis showed that morphine and tramadol produced different effects. While morphine caused a downregulation of prodynorphin mRNA levels in all investigated areas (hypothalamus, hippocampus, and striatum), tramadol did not cause any significant change in the striatum, and did not decrease prodynorphin biosynthesis in the hypothalamus and in the hippocampus, at nontoxic doses (10 and 20 mg/kg). The highest dose of tramadol (80 mg/kg) decreased prodynorphin mRNA levels in the hypothalamus and the hippocampus but not in the striatum. These data give some information on tramadol effects at molecular level in the CNS. They indicate that the alterations of prodynorphin gene expression caused by tramadol and morphine show a different pattern that may be related to the different abuse potential of the two analgesic drugs.

Effects of dextromethorphan on in vitro contractile responses of mouse and rat urinary bladders

Dextromethorphan (DXM) is a cough-suppressing ingredient in a variety of over-the-counter cough and cold medications. Dextromethorphan elevates the threshold for coughing primarily through a central mechanism. At doses recommended for treating coughs the drug is safe and effective. At much higher doses, DXM produces dissociative effects similar to those of phencyclidine and ketamine. Opioid analgesics structurally related to DXM also inhibit bladder contractions and produce urinary retention through a non-opioid mechanism. This study evaluated the direct effects of DXM on in vitro contractile responses of rat and mouse urinary bladders. Male rats and mice were anaesthetized and their bladders removed. Bladder strips were suspended in 15 ml oxygenated Tyrode's solution containing glucose. Bladder strip contractions were evoked by field stimulation (FS), carbachol or elevated KCl concentrations and contractile responses recorded. The strips were then exposed to 3 microM (DXM) for 30 min and re-stimulated. This sequence was repeated at 10, 30, and 100 microM DXM. (a) The rat bladder generated significantly greater tension than the mouse bladder. (b) Dextromethorphan produced a dose-dependent inhibition of the response to FS that was approximately equal for rat and mouse bladders. FS at 8 or 32 Hz was significantly more sensitive to DXM inhibition than 2 Hz. (c) The response to carbachol was more sensitive to inhibition by DXM than the responses to FS or KCl. These results demonstrate that DXM inhibits bladder contractions in vitro and that mouse and rat bladders are affected to approximately the same extent.