Peripheral Opioid Receptors Research Articles

An endomorphine analog ([d-Ala(2)]-Endomorphin 2, TAPP) lowers blood pressure and enhances tissue nitric oxide in anesthetized rats.

Activation of opioid receptors can alter cardiovascular function, an action possibly mediated by nitric oxide (NO). In this study we examined the effects of ([d-Ala(2)]-Endomorphin 2, TAPP), a synthetic opioid μ-receptor agonist, on blood pressure (MABP), tissue NO bioavailability and renal hemodynamics and excretion. In acute experiments with anesthetized normotensive male Sprague-Dawley rats TAPP was given as a short iv infusion at a dose of 1.2 or 12mg/kg and then MABP, renal medullary NO signal (polarographic electrode), total renal blood flow (RBF, renal artery Transonic probe), renal regional perfusion (laser-Doppler fluxes) and renal excretion were simultaneously measured over 2h. After 1.2mg/kg dose MABP decreased progressively from 121±7 to 114±9mmHg (-6%, p<0.05) while kidney tissue NO signal increased from 29.1±2.7 to 31.7±3.1nA (6%, p<0.04). Both effects were prevented by Naloxone methiodide, a peripheral opioid receptor inhibitor. RBF and renal regional perfusion were not altered by either dose of TAPP; renal sodium excretion changes were highly variable and were not affected by Naloxone pretreatment. Briefly, we found that in anesthetized normotensive rats stimulation of peripheral opioid receptors with TAPP caused a prolonged decrease in arterial pressure, a change that was associated and probably causally related to an increase in tissue NO. The data suggest that synthetic opioids that do not penetrate the blood-brain barrier and are potentially non-addictive could be considered for antihypertensive therapy.

Nalbuphine versus Dexmedetomidine as an Analgesic Additive to Lidocaine in Intravenous Regional Anesthesia IVRA

Intravenous Regional Anesthesia (IVRA) is easy to administer and reliable. But delayed onset and lack of postoperative analgesia are the major limitations. Accordingly, many additives have been tried. Dexmedetomidine is a highly selective α-2 adrenoceptor agonist. Addition of dexmedetomidine to lignocaine is effective in decreasing the anesthetic requirements and prolonging the analgesic duration. On the other hand, many theories explain that opioids may exert their peripheral action through peripheral opioid receptors. The aim of the study was to compare the analgesic efficacy of nalbuphine and dexmedetomidine when used separately as adjuvants to lidocaine during IVRA with the effect of lidocaine alone. Sixty adult patients, who were scheduled for surgery of the hand or the forearm under intravenous regional anesthesia, were included in this study. The patients were randomly allocated into three equal groups. The syringes in all groups contained 3 mg/kg of lidocaine 0.5% diluted in 40 ml isotonic saline. Group C: Control group. Group D: Dexmedetomidine group, 1 mic/kg dexmedetomidine diluted was added. Group N: Nalbuphine group, 20 mg nalbuphine was added. Sensory onset time (min) as well as motor block onset time (min) were significantly shorter in Groups N (2.0 ± 1.7) (3.8 ± 2.1) respectively, and D (2.2 ± 1.8) (4.6 ± 2.2) respectively compared to Group C (3.6 ± 1.6) (7.1 ± 1.4) (P < 0.05), with no significant differences between nalbuphine and dexmedetomidine groups. Sensory and motor block recovery times (min) were significantly longer in Groups N (9.6 ± 0.7) (10.3 ± 1.2) and D (8.1 ± 1.1) (9.1 ± 2.1) when compared to Group C (3.4 ± 2.1) (3.7 ± 3.1) (P < 0.05), without significant differences between nalbuphine and dexmedetomidine. Ramsay sedation score was significantly higher (RSS = 2) in 14 patients (70%) in Group D compared to Groups C and N during the first 30 min after the release of tourniquet.

Evaluating topical opioid gel on donor site pain: A small randomised double blind controlled trial

BackgroundAutologous donor skin harvested for transplantation is a common procedure in patients with burns, and patients often feel more pain at the donor site than is justified by the extent of trauma. Topical morphine gels have been thought to have an effect on peripheral opioid receptors by creating antinociceptive and anti-inflammatory effects, which could potentially reduce the systemic use of morphine-like substances and their adverse effects. MethodsWe therefore did a paired, randomised, double-blind placebo study to investigate the effect of morphine gel and placebo on dual donor sites that had been harvested in 13 patients. Pain was measured on a visual analogue scale (VAS) 15 times in a total of 5 days. ResultsThe mean (SD) VAS was 1.6 (2.3) for all sites, 1.5 (2.2) for morphine, and 2.0 (2.5) for placebo. The pain relieving effects of morphine gel were not significantly better than placebo. ConclusionThe assessment of pain at donor sites is subjective, and more systematic and objective studies are needed.

Differences in the morphine-induced inhibition of small and large intestinal transit: Involvement of central and peripheral μ-opioid receptors in mice

Constipation is the most common side effect of morphine. Morphine acts centrally and on peripheral sites within the enteric nervous system. There are a few comprehensive studies on morphine-induced constipation in the small and large intestine by the activation of central and peripheral μ-opioid receptors. We investigated the differences in the inhibition of the small and large intestinal transit in normal and morphine-tolerant mice. Morphine reduced the geometric center in the fluorescein isothiocyanate–dextran assay and prolonged the bead expulsion time in a dose-dependent manner. The inhibitory effects of morphine were blocked by μ-opioid antagonist β-funaltrexamine, but not by δ- and κ-opioid antagonists. The peripheral opioid receptor antagonist, naloxone methiodide, partially blocked morphine's effect in the small intestine and completely blocked its effect in the large intestine. The intracerebroventricular administration of naloxone significantly reversed the delay of small intestinal transit but did not affect morphine-induced inhibition of large intestinal transit. Naloxone methiodide completely reversed the inhibition of large intestinal transit in normal and morphine-tolerant mice. Naloxone methiodide partially reversed the morphine-induced inhibition of small intestinal transit in normal mice but completely reversed the effects of morphine in tolerant mice. Chronic treatment with morphine results in tolerance to its inhibitory effect on field-stimulated contraction in the isolated small intestine but not in the large intestine. These results suggest that peripheral and central opioid receptors are involved in morphine-induced constipation in the small and large intestine during the early stage of treatment, but the peripheral receptors mainly regulate constipation during long-term morphine treatment.

Erratum to: Role of central and peripheral opioid receptors in the cardioprotection of intravenous morphine preconditioning.

Both central and peripheral opioid receptors activation produce cardioprotection. This study investigates the role of central and peripheral opioid receptors in intravenous morphine preconditioning (MPC) and ischemic preconditioning (IPC).Sixty-five anesthetized, open chests, male Sprague-Dawley rats were assigned to one of nine groups after intrathecal catheter placement. IPC was induced by three cycles of intermittent occlusion of left anterior descending artery (5 min occlusion interspersed with 5 min of reperfusion). MPC was induced by three consecutive intravenous infusions of 100 μg/kg morphine over five minutes. The opioid receptors antagonist naloxone methiodide (NM), was intravenously or intrathecally, at a dose of 20 mg/kg or 20 μg/kg, given 10 min before IPC or MPC (IVNM + IPC, ITNM + IPC, IVNM + MPC, ITNM +MPC). Control group (CON) and intravenously or intrathecally administered NM (IVNM, ITNM) were used as negative controls, respectively. All hearts were subjected to 30 min of ischemia follow by 2 h of reperfusion. Infarct size, as a percentage of the area at risk, was determined by 2, 3, 5-triphenyltetrazolium staining. Heart rate and mean arterial blood pressure were monitored.The infarct size was significantly reduced in the IPC and MPC groups compared with control. The additional of intravenous or intrathecal NM both reversed the cardioprotective effects of MPC. In comparison only intravenous administration of NM before IPC could attenuate the cardioprotection.MPC could mimic IPC, produce a similar cardioprotective effect. Both central and peripheral opioid receptors mediate in the cardioprotection of MPC, however, only peripheral opioid receptors in IPC.

Poster 147 CR845, a Peripheral Kappa Opioid Receptor Agonist, Provides Better Pain Relief With Less Nausea and Vomiting Than Placebo in Patients After Bunionectomy

PM&RVolume 7, Issue 9S p. S140-S140 Pain and Spine Medicine Poster 147 CR845, a Peripheral Kappa Opioid Receptor Agonist, Provides Better Pain Relief With Less Nausea and Vomiting Than Placebo in Patients After Bunionectomy Frédérique Menzaghi PhD, Frédérique Menzaghi PhD Cara Therapeutics, Inc., Shelton, CT, United StatesSearch for more papers by this authorRobert H. Spencer PhD, Robert H. Spencer PhD Cara Therapeutics, Inc., Shelton, CT, United StatesSearch for more papers by this authorJoseph W. Stauffer DO, MBA, Joseph W. Stauffer DO, MBA Cara Therapeutics, Inc., Shelton, CT, United StatesSearch for more papers by this authorPaul J. Tiseo PhD, Paul J. Tiseo PhD Cara Therapeutics, Inc., Shelton, CT, United StatesSearch for more papers by this authorNacer E.D. Abrouk PhD, Nacer E.D. Abrouk PhD Cara Therapeutics, Inc., Shelton, CT, United StatesSearch for more papers by this author Frédérique Menzaghi PhD, Frédérique Menzaghi PhD Cara Therapeutics, Inc., Shelton, CT, United StatesSearch for more papers by this authorRobert H. Spencer PhD, Robert H. Spencer PhD Cara Therapeutics, Inc., Shelton, CT, United StatesSearch for more papers by this authorJoseph W. Stauffer DO, MBA, Joseph W. Stauffer DO, MBA Cara Therapeutics, Inc., Shelton, CT, United StatesSearch for more papers by this authorPaul J. Tiseo PhD, Paul J. Tiseo PhD Cara Therapeutics, Inc., Shelton, CT, United StatesSearch for more papers by this authorNacer E.D. Abrouk PhD, Nacer E.D. Abrouk PhD Cara Therapeutics, Inc., Shelton, CT, United StatesSearch for more papers by this author First published: 08 September 2015 https://doi.org/10.1016/j.pmrj.2015.06.185Citations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume7, Issue9SSeptember 2015Pages S140-S140 RelatedInformation

An antihypertensive opioid: Biphalin, a synthetic non-addictive enkephalin analog decreases blood pressure in spontaneously hypertensive rats.

Endogenous opioid systems may be engaged in the control of arterial pressure (MAP), however, given the risk of addiction, opioid receptor agonists are not used in antihypertensive therapy. We examined cardiovascular effects of biphalin, a potentially non-addictive dimeric enkephalin analog, an agonist of opioid μ and δ receptors. Biphalin was infused iv at 150μg/kg/h to anesthetized spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Along with MAP and heart rate (HR), renal blood flow (RBF) and iliac blood flow (IBF, a measure of hind limb perfusion) were measured using Transonic probes on renal and iliac artery, respectively. The effects of biphalin were compared with those of intravenous morphine (1.5mg/kg/h). In two SHR groups biphalin decreased MAP from 143±2 to 130±2 and from 177±4 to 167±3mmHg (p<0.001) while HR did not change or modestly decreased. The renal blood flow (RBF) increased modestly and both renal and hind limb vascular resistances decreased significantly (p<0.001). The responses were blocked by inhibition of peripheral opioid receptors with naloxone methiodide. Unlike in SHR, in WKY rats biphalin did not change MAP or vascular resistances. Morphine infusion decreased MAP in SHR from 169±6 to 150±6mmHg (less decrease in WKY) and significantly decreased RBF and IBF. Since biphalin, a non-addictive synthetic opioid, lowers MAP in SHR, a model of hypertension with pronounced neurogenic component, such analogs might find therapeutic application in human stress-induced hypertensive states. Biphalin's advantage is no associated reduction of renal perfusion.

O efeito analgésico de tramadol não é mediado por receptores opioides na dor de ratos no pós‐operatório imediato

Background and objectivesTramadol is known as a central acting analgesic drug, used for the treatment of moderate to severe pain. Local analgesic effect has been demonstrated, in part due to local anesthetic‐like effect, but other mechanisms remain unclear. The role of peripheral opioid receptors in the local analgesic effect is not known. In this study, we examined role of peripheral opioid receptors in the local analgesic effect of tramadol in the plantar incision model. MethodsYoung male Wistar rats were divided into seven groups: control, intraplantar tramadol, intravenous tramadol, intravenous naloxone‐intraplantar tramadol, intraplantar naloxone‐intraplantar tramadol, intravenous naloxone‐intravenous tramadol, and intravenous naloxone. After receiving the assigned drugs (tramadol 5mg, naloxone 200μg or 0.9% NaCl), rats were submitted to plantar incision, and withdrawal thresholds after mechanical stimuli with von Frey filaments were assessed at baseline, 10, 15, 30, 45 and 60min after incision. ResultsPlantar incision led to marked mechanical hyperalgesia during the whole period of observation in the control group, no mechanical hyperalgesia were observed in intraplantar tramadol group, intraplantar naloxone‐intraplantar tramadol group and intravenous naloxone‐intraplantar tramadol. In the intravenous tramadol group a late increase in withdrawal thresholds (after 45min) was observed, the intravenous naloxone‐intravenous tramadol group and intravenous naloxone remained hyperalgesic during the whole period. ConclusionsTramadol presented an early local analgesic effect decreasing mechanical hyperalgesia induced by plantar incision. This analgesic effect was not mediated by peripheral opioid receptors.

Emerging therapies for patients with symptoms of opioid-induced bowel dysfunction.

Opioid-induced bowel dysfunction (OIBD) comprises gastrointestinal (GI) symptoms, including dry mouth, nausea, vomiting, gastric stasis, bloating, abdominal pain, and opioid-induced constipation, which significantly impair patients’ quality of life and may lead to undertreatment of pain. Traditional laxatives are often prescribed for OIBD symptoms, although they display limited efficacy and exert adverse effects. Other strategies include prokinetics and change of opioids or their administration route. However, these approaches do not address underlying causes of OIBD associated with opioid effects on mostly peripheral opioid receptors located in the GI tract. Targeted management of OIBD comprises purely peripherally acting opioid receptor antagonists and a combination of opioid receptor agonist and antagonist. Methylnaltrexone induces laxation in 50%–60% of patients with advanced diseases and OIBD who do not respond to traditional oral laxatives without inducing opioid withdrawal symptoms with similar response (45%–50%) after an oral administration of naloxegol. A combination of prolonged-release oxycodone with prolonged-release naloxone (OXN) in one tablet (a ratio of 2:1) provides analgesia with limited negative effect on the bowel function, as oxycodone displays high oral bioavailability and naloxone demonstrates local antagonist effect on opioid receptors in the GI tract and is totally inactivated in the liver. OXN in daily doses of up to 80 mg/40 mg provides equally effective analgesia with improved bowel function compared to oxycodone administered alone in patients with chronic non-malignant and cancer-related pain. OIBD is a common complication of long-term opioid therapy and may lead to quality of life deterioration and undertreatment of pain. Thus, a complex assessment and management that addresses underlying causes and patomechanisms of OIBD is recommended. Newer strategies comprise methylnaltrexone or OXN administration in the management of OIBD, and OXN may be also considered as a preventive measure of OIBD development in patients who require opioid administration.

El efecto analgésico del tramadol no está mediado por receptores opiáceos en el dolor en ratones en el postoperatorio inmediato

Background and objectivesTramadol is known as a central acting analgesic drug, used for the treatment of moderate to severe pain. Local analgesic effect has been demonstrated, in part due to local anesthetic-like effect, but other mechanisms remain unclear. The role of peripheral opioid receptors in the local analgesic effect is not known. In this study, we examined role of peripheral opioid receptors in the local analgesic effect of tramadol in the plantar incision model. MethodsYoung male Wistar rats were divided into seven groups: control, intraplantar tramadol, intravenous tramadol, intravenous naloxone-intraplantar tramadol, intraplantar naloxone-intraplantar tramadol, intravenous naloxone-intravenous tramadol, and intravenous naloxone. After receiving the assigned drugs (tramadol 5mg, naloxone 200μg or 0.9% NaCl), rats were submitted to plantar incision, and withdrawal thresholds after mechanical stimuli with von Frey filaments were assessed at baseline, 10, 15, 30, 45 and 60min after incision. ResultsPlantar incision led to marked mechanical hyperalgesia during the whole period of observation in the control group, no mechanical hyperalgesia were observed in intraplantar tramadol group, intraplantar naloxone-intraplantar tramadol group and intravenous naloxone-intraplantar tramadol. In the intravenous tramadol group a late increase in withdrawal thresholds (after 45min) was observed, the intravenous naloxone-intravenous tramadol group and intravenous naloxone remained hyperalgesic during the whole period. ConclusionsTramadol presented an early local analgesic effect decreasing mechanical hyperalgesia induced by plantar incision. This analgesic effect was not mediated by peripheral opioid receptors.

Involvement of the NO/cGMP/KATP pathway in the antinociceptive effect of the new pyrazole 5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)-2H-tetrazole (LQFM-021)

The pyrazol compounds are known to possess antipyretic, analgesic and anti-inflammatory activities. This study was conducted to investigate the peripheral antinociceptive effect of the pyrazole compound 5-(1-(3-Fluorophenyl)-1H-pyrazol-4-yl)-2H-tetrazole (LQFM-021) and involvement of opioid receptors and of the NO/cGMP/KATP pathway. The oral treatments in mice with LQFM-021 (17, 75 or 300 mg/kg) decreased the number of writhing. In the formalin test, the treatments with LQFM-021 at doses of 15, 30 and 60 mg/kg reduced the licking time at both neurogenic and inflammatory phases of this test. The treatment of the animals with LQFM-021 (30 mg/kg) did not have antinociceptive effects in the tail-flick and hot plate tests. Furthermore, pre-treatment with naloxone (3 mg/kg i.p.), L-name (10 mg/kg i.p.), ODQ (10 mg/kg i.p.) or glibenclamide (3 mg/kg i.p.) antagonized the antinociceptive effect of LQFM-021 in both phases of the formalin test. In addition, it was also demonstrated that the treatments of mice with LQFM-021(15, 30 and 60 mg/kg) did not compromise the motor activity of the animals in the chimney test. Only the highest dose used in the antinociceptive study promoted changes in the open field test and pentobarbital-induced sleep test, thus ruling out possible false positive effects on nociception tests. Our data suggest that the peripheral antinociception effects of the LQFM-021 were mediated through the peripheral opioid receptors with activation of the NO/cGMP/KATP pathway.

Effect of peptide agonists of peripheral opioid receptors on operant feeding behavior and food motivation in rats.

We studied the effect of intragastric administration of peptide agonists of μ-opioid receptors (DAMGO) and δ-opioid receptors (DADLE) on food consumption and food motivation during operant feeding behavior of different intensity and effectiveness. To obtain one food granule, trained rats should press a lever 1 time (day 1), 2 times (day 2), 4 times (day 3), 8 times (day 4), 16 times (day 5), or 32 times (day 6). Activation of δ-opioid receptors in the stomach was followed by suppression of feeding behavior at low energy expenditure. The level of food motivation under these conditions practically did not differ from the control. Activation of μ-opioid receptors in the stomach suppressed energy-consuming feeding behavior, which was accompanied by an increase in the level of food motivation. It can be hypothesized that protein metabolites exhibiting μ-opioid activity probably provide afferent signals into CNS via the vagus nerve to terminate energy expenditure under adverse conditions (although food motivation is not satisfied). Food motivation under these conditions probably contributes to the behavior aimed towards the search for more available food.

Dual regulation of δ-opioid receptor function by arachidonic acid metabolites in rat peripheral sensory neurons.

The regulation of opioid receptor system function in peripheral sensory neurons is not well understood. Opioid agonist efficacy to inhibit nociceptor function and to promote antinociception is generally weak under basal conditions and frequently no response occurs. However, in response to a cyclooxygenase-dependent metabolite of arachidonic acid (AA) after exposure to inflammatory mediators, such as bradykinin (BK) or exogenous AA, peripheral opioid receptor systems become much more responsive to opioid agonists. In this study, we examined the time course for the induction and maintenance of functional competence of the δ-opioid receptor (DOR) system in adult rat nociceptors in culture and in vivo. We found that the responsive state of DOR after pretreatment with BK or exogenous AA is transient (30-60 minutes) and persists for 15-30 minutes after a 15-minute exposure of nociceptors to BK or AA. Interestingly, whereas functional competence of the DOR system could be reinduced with a second application of BK 60 minutes after the first, responsiveness of the DOR system could not be reinduced after an initial exposure to AA. This nonresponsive state of DOR after exogenous AA was mediated by a lipoxygenase (LOX)-dependent metabolite of AA. Intraplantar carrageenan also produced transient DOR functional competence and responsiveness was also reinduced by inhibition of LOX. Thus, the DOR system expressed by peripheral sensory neurons is under dual regulation by cyclooxygenase- and LOX-dependent metabolites of AA.

Long-lasting oral analgesic effects of N-protected aminophosphinic dual ENKephalinase inhibitors (DENKIs) in peripherally controlled pain.

The peripheral endogenous opioid system is critically involved in neuropathic and inflammatory pain generation as suggested by the modulation of opioid receptors expression and enkephalins (ENKs) release observed in these painful conditions. Accordingly, an innovative approach in the treatment of these nocifensive events is to increase and maintain high local concentrations of extracellular pain-evoked ENKs, by preventing their physiological enzymatic inactivation by two Zn metallopeptidases, the neutral endopeptidase (NEP, neprilysin, EC 3.4.24.11) and the neutral aminopeptidase (APN, EC 3.4.11.2). With this aim, new orally active dual ENKephalinase inhibitors (DENKIs) were designed as soluble prodrugs by introducing a N-terminal cleavable carbamate in the previously described aminophosphinic inhibitors. This induces long-lasting antinociceptive responses after oral administration, in various rodent models of inflammatory and neuropathic pain. These responses are mediated through stimulation of peripheral opioid receptors by DENKIs-protected ENKs as demonstrated by naloxone methiodide reversion. In all tested models, the most efficient prodrug 2a (PL265) was active, at least during 150–180 min, after single oral administration of 25–50 mg/kg in mice and of 100–200 mg/kg in rats. In models of neuropathic pain, both hyperalgesia and allodynia were markedly reduced. Interestingly, combination of inactive doses of 2a (PL265) and of the anti-epileptic drug gabapentin had synergistic effect on neuropathic pain. Pharmacokinetic studies of 2a (PL265) in rats show that the active drug is the only generated metabolite produced. These encouraging results have made 2a (PL265) a suitable candidate for clinical development.

Buprenorphine for postoperative analgesia: Axillary brachial plexus block versus intramuscular administration in a placebo-controlled trial

Background and Aims:Peripheral administration of opioids has been suggested for prolongation of regional analgesia. This prospective, randomized, double-blind placebo-controlled study was undertaken to compare the effect of regional (axillary brachial plexus block [ABPB]) versus intramuscular (IM) buprenorphine (2 μg/kg) in adults.Material and Methods:Seventy-five adults undergoing upper limb surgery received ABPB with local anaesthetic (15 ml 0.5% bupivacaine, 15 ml 2% lignocaine with adrenaline 1:200,000, 9 ml normal saline [NS]). In addition, regional group RB (n = 25) received buprenorphine 2 μg/kg in ABPB and 1 ml NS IM. Systemic Group SB (n = 25) received 1 ml NS in ABPB and buprenorphine 2 μg/kg IM. Group C (n = 25) received 1 ml NS in ABPB and IM. Onset, duration of sensory and motor block, hemodynamic parameters, sedation score, pain scores using visual analog scale, duration of postoperative analgesia, rescue analgesic (RA) requirement, adverse events, and patient satisfaction were noted.Results:Demographics, onset and duration of sensory, motor block were similar. RB group had longest duration of analgesia (20.61 ± 1.33 h) compared to SB (10.91 ± 0.90 h) and control group (5.86 ± 0.57 h) (P < 0.05 RB vs. SB/C and SB vs. C). RA requirement was highest in the control group and least in RB group (P = 0.000 RB vs. SB/C and SB vs. C). SB group had a maximum number of side effects (P = 0.041, SB vs. RB/C). Patient satisfaction was highest with group RB (P < 0.05 RB vs. SB/C, and P = 0.06 SB vs. C).Conclusion:Buprenorphine 2 μg/kg in axillary plexus block provides significantly prolonged analgesia with less RA requirement and greater patient satisfaction compared to IM administration. This is highly suggestive of action on peripheral opioid receptors.

Effect of plantar subcutaneous administration of bergamot essential oil and linalool on formalin-induced nociceptive behavior in mice.

This study investigated the effect of bergamot essential oil (BEO) or linalool, a major volatile component of BEO, on the nociceptive response to formalin. Plantar subcutaneous injection of BEO or linalool into the ipsilateral hindpaw reduced both the first and late phases of the formalin-induced licking and biting responses in mice. Plantar subcutaneous injection of BEO or linalool into the contralateral hindpaw did not yield an antinociceptive effect, suggesting that the antinociceptive effect of BEO or linalool in the formalin test occurred peripherally. Intraperitoneal and plantar subcutaneous injection pretreatment with naloxone hydrochloride, an opioid receptor antagonist, significantly attenuated both BEO- and linalool-induced antinociception. Pretreatment with naloxone methiodide, a peripherally acting opioid receptor antagonists, also significantly antagonized the antinociceptive effects of BEO and linalool. Our results provide evidence for the involvement of peripheral opioids in antinociception induced by BEO and linalool. These results suggest that activation of peripheral opioid receptors may play an important role in reducing formalin-induced nociception.

Development of an Effective Topical Liposomal Formulation for Localized Analgesia and Antiinflammatory Actions in the Complete Freund’s Adjuvant Rodent Model of Acute Inflammatory Pain

Background: Peripheral opioid receptor targeting has been well established as a novel target in clinical pain management for acute and chronic peripheral inflammatory pain. The physiochemical properties of the peripheral mu-opioid receptor agonist, loperamide HCl, limit the use of the free drug as an analgesic or anti-inflammatory agent, particularly for dermal delivery across intact skin. Objective: Our objective was to manufacture an effective topical formulation containing loperamide using liposomal delivery that would allow loperamide to produce analgesia and anti-inflammatory effects, by penetrating the epidermis to reach peripheral opioid receptors within the dermis of intact skin. Study Design: A randomized, double blind, controlled animal trial. Methods: Thirty-five adult male Wistar rats (200 – 250 g) were randomly divided into 5 groups: loperamide HCl-encapsulated liposomal gel, naloxone methiodide + loperamide HCl-encapsulated liposomal gel, free loperamide gel, empty liposomal gel, and 1% diclofenac gel (Voltaren®). Diclofenac gel was used as a positive control as it is clinically used as a topical analgesic and anti-inflammatory drug. Animals received an intraplantar injection of 150 µl Complete Freund’s Adjuvant (CFA) into the right hindpaw and experiments were performed 5 days post-CFA injection, which corresponded to the peak inflammatory response. All manufactured formulations were applied topically on both hind paws twice daily, whereas Voltaren gel was applied 3 times a day in accordance with the manufacturer’s instructions. The dose administered was 50 µl, which equated to 0.4 mg of loperamide HCl for the loperamide HCl treatment groups (low dose). Naloxone methiodide (1 mg/kg) was administered via intraplantar injection, 15 minutes prior to application of loperamide HCl-encapsulated liposomal gel to determine opioid receptor dependent activity. An investigator blinded to the treatment administered assessed time course of the antinociceptive and antiinflammatory effects using a paw pressure analgesiometer and plethysmometer, respectively. Results: Application of loperamide HCl in a liposomal gel formulation exerted analgesic and antiinflammatory effects exclusively in peripheral painful inflamed tissue. This formulation produced highly significant analgesic and anti-inflammatory effects over the 48-hour time course studied following topical administration in rats with CFA-induced inflammation of the paw. As expected, the diclofenac gel group showed significant antinociception over the duration of the study; however, this effect was lower in comparison to the loperamide HCl liposomal gel formulation. All other control groups showed no significant antinociceptive effects. In addition, all control groups (1% diclofenac gel, free loperamide gel, and empty liposomal gel) did not demonstrate a significant change in paw volume over 48 hours. Limitations: In vivo studies were performed in the well-established rodent model of acute inflammatory pain. We are currently studying this approach in chronic pain models known to have clinical activation of the peripheral immune-derived opioid response. Conclusions: The study demonstrates that topically applied loperamide encapsulated within liposomal systems has improved therapeutic efficacy over conventional formulations for the local treatment of acute peripheral inflammatory pain conditions where the skin has remained intact. Once in the inflamed peripheral tissue, loperamide provides analgesic and anti-inflammatory effects in a similar manner to peripheral endogenous opioids. This preparation optimises the retention of drug at the site where action is required. Key words: Pain, inflammation, opioids, loperamide, liposomes, topical drug delivery, peripheral opioid receptors

Quality of life and healthcare resource in patients receiving opioids for chronic pain: a review of the place of oxycodone/naloxone.

In patients managed with opioids for chronic pain, opioid-induced bowel dysfunction—specifically, opioid-induced constipation (OIC)—is a common side effect, which has a significant impact on quality of life (QoL). The most recent developments for management of OIC are opioid antagonists, including naloxone, a competitive antagonist of peripheral opioid receptors that reverses opioid-induced peripheral gastrointestinal (GI) effects. A prolonged-release formulation of naloxone is available in combination with oxycodone (OXN PR). To review the specific role of OXN PR in the management of chronic pain and OIC and its impact on QoL and healthcare costs, a review of available relevant literature was conducted. Healthcare costs can be up to ten times higher for patients with GI events than for those without. Assessment of QoL in patients with OIC is essential, and multiple tools for its evaluation are available. The Bowel Function Index (BFI), a tool that was specifically developed and validated to measure bowel function in patients with OIC, can be an indication of QoL. In patients with moderate-to-severe chronic pain, randomized trials have demonstrated that OXN PR has equal analgesic efficacy and safety, but results in improved bowel function, compared with prolonged-release oxycodone (Oxy PR) alone. In conclusion, randomized studies using the BFI, as well as real-world clinical practice observations, have demonstrated improved QoL for patients taking OXN PR. This combination should allow more patients to benefit from the analgesic efficacy of opioid therapy and should minimize the side effects of constipation that correspond to improvements in QoL and healthcare offsets.

Local analgesic effect of tramadol is not mediated by opioid receptors in early postoperative pain in rats

Background and objectivesTramadol is known as a central acting analgesic drug, used for the treatment of moderate to severe pain. Local analgesic effect has been demonstrated, in part due to local anesthetic-like effect, but other mechanisms remain unclear. The role of peripheral opioid receptors in the local analgesic effect is not known. In this study, we examined role of peripheral opioid receptors in the local analgesic effect of tramadol in the plantar incision model. MethodsYoung male Wistar rats were divided into seven groups: control, intraplantar tramadol, intravenous tramadol, intravenous naloxone-intraplantar tramadol, intraplantar naloxone-intraplantar tramadol, intravenous naloxone-intravenous tramadol, and intravenous naloxone. After receiving the assigned drugs (tramadol 5mg, naloxone 200μg or 0.9% NaCl), rats were submitted to plantar incision, and withdrawal thresholds after mechanical stimuli with von Frey filaments were assessed at baseline, 10, 15, 30, 45 and 60min after incision. ResultsPlantar incision led to marked mechanical hyperalgesia during the whole period of observation in the control group, no mechanical hyperalgesia were observed in intraplantar tramadol group, intraplantar naloxone-intraplantar tramadol group and intravenous naloxone-intraplantar tramadol. In the intravenous tramadol group a late increase in withdrawal thresholds (after 45min) was observed, the intravenous naloxone-intravenous tramadol group and intravenous naloxone remained hyperalgesic during the whole period. ConclusionsTramadol presented an early local analgesic effect decreasing mechanical hyperalgesia induced by plantar incision. This analgesic effect was not mediated by peripheral opioid receptors.

Opioid receptor bronchial tree: current science.

Systemic opioids have the evidence to support their use in refractory dyspnea; however, the mechanisms of how they exert their effects are not fully understood. The relevance of peripheral mechanisms, in part, is still questioned, especially as a meta-analysis demonstrated no benefit from nebulized opioids. This might be related to the lack of standardization of the inhalation methods. There is a need to clarify whether peripheral opioid receptors may serve as the target for inhaled treatment and what are the potential peripheral mechanisms of opioids. Opioidergic systems are present in structures important for the regulation of bronchial and pulmonary vascular responses, as well as breathlessness perception in the human respiratory system. Opioid receptors located in the pulmonary neuroendocrine cells (PNECs) and sensory C-fibers within the bronchial epithelium are easily accessible for inhaled treatment. Morphine administrated by a pneumodosimetric method shows a different pharmacokinetic profile to those described for systemic routes, suggesting local metabolism in lung. Research suggests that peripheral opioid receptors in lungs may be utilized as a target for therapeutic interventions. According to this hypothesis, to achieve breathlessness relief, opioids should be administered in close proximity to their receptors in the PNECs and sensory C-fibers of the bronchial epithelium.