u-50488 and Nociceptive-Pain

The pivotal role of the stereocenter at the N-substituent of the 6,7-benzomorphan scaffold was investigated combining synthetic and pharmacological approaches. 2R- and 2S-diastereoisomers of the multitarget MOR/DOR antinociceptive ligand LP2 (1) were synthesized and their pharmacological profile was evaluated in in vitro and vivo assays. From our results, 2S-LP2 (5) showed an improved pharmacological profile in comparison to LP2 (1) and 2R-LP2 (4). 2S-LP2 (5) elicited an antinociceptive effect with a 1.5- and 3-times higher potency than LP2 (1) and R-antipode (4), respectively. In vivo effect of 2S-LP2 (5) was consistent with the improved MOR/DOR efficacy profile assessed by radioligand binding assay, to evaluate the opioid receptor affinity, and BRET assay, to evaluate the capability to promote receptor/G-protein and receptor/β-arrestin 2 interaction. 2S-LP2 (5) was able to activate, with different efficacy, G-protein pathway over β-arrestin 2, behaving as biased agonist at MOR and mainly at DOR. Considering the therapeutic potential of both multitarget MOR/DOR agonism and functional selectivity over G-protein, the 2S-LP2 (5) biased multitarget MOR/DOR agonist could provide a safer treatment opportunity.

Topics: Analgesics, Opioid; Animals; Benzomorphans; Dose-Response Relationship, Drug; Drug Discovery; Humans; Mice; Molecular Structure; Nociceptive Pain; Pain Measurement; Receptors, Opioid, delta; Receptors, Opioid, mu; Structure-Activity Relationship

Carrageenan-induced hyperalgesia is a widely used pain model in rodents. However, characteristics of carrageenan-induced hyperalgesia and effects of analgesic drugs under these conditions are unknown in nonhuman primates.. The aims of this study were to develop carrageenan-induced hyperalgesia in rhesus monkeys and determine the efficacy and potency of agonists selective for the four opioid receptor subtypes in this model versus acute pain, as compared to non-steroidal anti-inflammatory drugs (NSAIDs).. Tail injection of carrageenan produced long-lasting thermal hyperalgesia in monkeys. Systemically administered agonists selective for opioid receptor subtypes, i.e., fentanyl (mu/MOP), U-50488H (kappa/KOP), SNC80 (delta/DOP) and Ro 64-6198 (nociceptin/orphanin FQ/NOP) dose-dependently attenuated carrageenan-induced thermal hyperalgesia with different potencies. In absence of carrageenan, these agonists, except SNC80, blocked acute thermal nociception. Opioid-related ligands, especially Ro 64-6198, were much more potent for their antihyperalgesic than antinociceptive effects. Both effects were mediated by the corresponding receptor mechanisms. Only fentanyl produced scratching at antihyperalgesic and antinociceptive doses consistent with its pruritic effects in humans, illustrating a translational profile of MOP agonists in nonhuman primates. Similar to SNC80, systemically administered NSAIDs ketorolac and naproxen dose-dependently attenuated carrageenan-induced hyperalgesia but not acute nociception.. Using two different pain modalities in nonhuman primates, effectiveness of clinically available analgesics like fentanyl, ketorolac and naproxen was distinguished and their efficacies and potencies were compared with the selective KOP, DOP, and NOP agonists. The opioid-related ligands displayed differential pharmacological properties in regulating hyperalgesia and acute nociception in the same subjects. Such preclinical primate models can be used to investigate novel analgesic agents.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Acute Pain; Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzamides; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fentanyl; Hyperalgesia; Imidazoles; Inflammation; Macaca; Male; Nociceptive Pain; Pain Measurement; Piperazines; Receptors, Opioid; Spiro Compounds

Psychological conditions affect pain responses in the human anterior cingulate cortex (ACC) according to brain imaging analysis. The rodent prefrontal cortex (PFC) including cingulate areas is also related to the affective dimension of pain. We previously reported PFC nociceptive responses inhibited by inputs from the amygdala, such as with dopamine (DA) D2 receptor (D2R) blockers, to show decreased effect on amygdala projections. In this study, we examined whether direct projections from the ventral tegmental area (VTA) to the PFC affect nociceptive responses in the PFC.. High frequency stimulation (HFS, 50 Hz, 30 s) delivered to the VTA produced long-lasting suppression (LLS) of nociceptive responses in the rat PFC including cingulate and prelimbic areas. Nociceptive responses evoked by mechanical pressure stimulation (2 s duration at 500 g constant force) applied to the tails of urethane-anesthetized rats were recorded using extracellular unit recording methods in the PFC. HFS delivered to the VTA, which has been reported to increase DA concentrations in the PFC, significantly suppressed nociceptive responses. The LLS of nociceptive responses persisted for about 30 minutes and recovered to the control level within 60 min after HFS. We also demonstrated local microinjection of a selective D2 agonist of DA receptors to induce LLS of mechanical nociceptive responses, while a D2 but not a D1 antagonist impaired the LLS evoked by HFS. In contrast, DA depletion by a 6-hydroxydopamine injection or a low concentration of DA induced by a κ-opiate receptor agonist injected into the VTA had minimal effect on nociceptive responses in the PFC.. HFS delivered to VTA inhibited nociceptive responses for a long period in PFC. DA D2R activation mediated by local D2 agonist injection also induced LLS of mechanical nociceptive responses. The mesocortical DA system may modify PFC nociceptive responses via D2 activity.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Action Potentials; Analgesics, Non-Narcotic; Animals; Biophysics; Dopamine; Dopamine Agents; Electric Stimulation; Functional Laterality; Male; Medial Forebrain Bundle; Neural Pathways; Nociceptive Pain; Physical Stimulation; Prefrontal Cortex; Rats; Rats, Wistar; Ventral Tegmental Area