87 research outputs found
Profiling the effects of repetitive morphine administration on motor behavior in rats
Efficient repetitive clinical use of morphine is limited by its numerous side effects, whereasanalgesic tolerance necessitates subsequent increases in morphine dose to achieve adequate levelsof analgesia. While many studies focused on analgesic tolerance, the effect of morphine dosing onnon-analgesic effects has been overlooked. This study aimed to characterize morphine-inducedbehavior and the development and progression of morphine-induced behavioral tolerance. Adultmale Sprague–Dawley rats were repetitively treated with subcutaneous morphine for 14 days in twodose groups (A: 5 mg/kg/day (b.i.d.) → 10 mg/kg/day; B: 10 mg/kg/day (b.i.d.) → 20 mg/kg/day).Motor behavior was assessed daily (distance traveled, speed, moving time, rearing, rotation) in anopen-field arena, before and 30 min post-injections. Antinociception was measured using tail-flickand hot-plate assays. All measured parameters were highly suppressed in both dosing groups onthe first treatment day, followed by a gradual manifestation of behavioral tolerance as the treatmentprogressed. Animals in the high-dose group showed increased locomotor activity after 10 days ofmorphine treatment. This excitatory phase converted to an inhibition of behavior when a highermorphine dose was introduced. We suggest that the excitatory locomotor effects of repetitive highdose morphine exposure represent a signature of its behavioral and antinociceptive tolerance
Strategies to Reduce Morphine Tolerance in Cancer: Evaluation of the Bifunctional Opioid UFP-505
Morphine is a gold-standard analgesic acting at MOP (μ) opioid receptors, producing analgesia and tolerance when administered chronically to patients (e.g.,cancer patients). If DOP (δ) opioid receptors are blocked at the same time that MOP is activated then analgesia with reduced tolerance results. UFP-505 (H-Dmt-Tic-Gly-NH-Bzl) is a synthetic pseudopeptide that interacts with MOP and DOP receptors (bifunctional). In a series of different models, we have characterized the pharmacological profile of UFP- 505 and we evaluated its antinociceptive properties in vivo.
In Chinese Hamster Ovary (CHO) cells stably expressing human MOP or DOP receptors, UFP-505 presented a full agonism and ultra-low partial agonism respectively.
UFP-505 caused a concentration-dependent internalization of MOP receptors, in contrast to morphine. Additionally, UFP-505 caused DOP receptor internalization similar to the full DOP agonist DPDPE. In a series of tail-flick assays using Wistar rats, acute intrathecal (i.t.) 10nmol UFP-505 produced strong antinociception, similar to 10nmol i.t. morphine. After 3 days of repeated administration, UFP-505 did not produce antinociceptive tolerance, in contrast to morphine. In neuronal tissue of treated animals, UFP-505 caused varying changes to opioid receptor mRNA levels, similar to morphine.
In the same model, UFP-505 induced MOP and DOP receptor internalization, whereas morphine failed to internalize the MOP receptors. UFP-505 also induced the internalization of MOP and DOP receptors in a novel CHO cell line stably expressing both receptors (produced as part of this project), in contrast to morphine.
Collectively this thesis has made a significant contribution to the field in that: 1) an extensive pharmacological in vitro and in vivo characterization is made; 2) a MOPagonist/DOP-partial agonist is shown to produce strong antinociception with no tolerance.
Further work on bifunctional opioids may lead to a better understanding of the mechanisms of analgesic tolerance and ligands like UFP-505 are good examples of prototypes for further development
Data on prolonged morphine-induced antinociception and behavioral inhibition in older rats
This article contains supportive data related to a research article entitled “Age-dependent antinociception and behavioral inhibition by morphine” (Paul et al., 2018) [1]. Antinociceptive latencies of 8 and 24-week old rats were obtained from tail-flick and hot plate assays after morphine treatment. Motor behavioral effects were measured at different time-points using automated infrared tracking in an open-field arena. Residual morphine content in post-mortem tissues were measured 240 min post-treatment. Concurrent measurements of antinociception, motor behavior and residual morphine content in post-mortem tissues of 8-week and 24-week old morphine-treated rats provide an integrated assessment of age-related differences
Simultaneous targeting of multiple opioid receptors: a strategy to improve side-effect profile
Opioid receptors are currently classified as mu (mu: mOP), delta (delta: dOP), kappa (kappa: kOP) with a fourth related non-classical opioid receptor for nociceptin/orphainin FQ, NOP. Morphine is the current gold standard analgesic acting at MOP receptors but produces a range of variably troublesome side-effects, in particular tolerance. There is now good laboratory evidence to suggest that blocking DOP while activating MOP produces analgesia (or antinociception) without the development of tolerance. Simultaneous targeting of MOP and DOP can be accomplished by: (i) co-administering two selective drugs, (ii) administering one non-selective drug, or (iii) designing a single drug that specifically targets both receptors; a bivalent ligand. Bivalent ligands generally contain two active centres or pharmacophores that are variably separated by a chemical spacer and there are several interesting examples in the literature. For example linking the MOP agonist oxymorphone to the DOP antagonist naltrindole produces a MOP/DOP bivalent ligand that should produce analgesia with reduced tolerance. The type of response/selectivity produced depends on the pharmacophore combination (e.g. oxymorphone and naltrindole as above) and the space between them. Production and evaluation of bivalent ligands is an emerging field in drug design and for anaesthesia, analgesics that are designed not to be highly selective morphine-like (MOP) ligands represents a new avenue for the production of useful drugs for chronic (and in particular cancer) pain
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