Pentazocine

Sigma-1 receptor antagonists promote antinociception in several models of pain, but the effects of sigma-1 agonists on nociception (particularly when the nociceptive system is primed) are not so well characterized; therefore we evaluated the effects of sigma-1 agonists on pain under different experimental conditions. The systemic administration of the selective sigma-1 agonists (+)-pentazocine and PRE-084, as well as the nonselective sigma-1 agonist carbetapentane (used clinically as an antitussive drug), did not alter sensitivity to mechanical stimulation under baseline conditions. However, they greatly promoted secondary mechanical allodynia after priming the nociceptive system with capsaicin. These effects of sigma-1 agonists were consistent in terms potency with the affinities of these drugs for sigma-1 receptors, were reversed by sigma-1 antagonists, and were not observed in sigma-1 knockout mice, indicating that they are sigma-1-mediated. Repeated systemic treatment with PRE-084 induced proallodynic effects even 24 h after treatment completion, but only after the nociceptive system was primed. However, neither the presence of this drug in the organism nor changes in sigma-1 receptor expression in areas involved in pain processing explains its long-term effects, suggesting that sustained sigma-1 agonism induces plastic changes in the nociceptive system that promote nociception.

Sigma-1 receptor (S1R) is an intracellular, multi-functional, ligand operated protein that also acts as a chaperone. It is considered as a pluripotent drug target in several pathologies. The publication of agonist and antagonist bound receptor structures has paved the way for receptor-based in silico drug design. However, recent studies on this subject payed no attention to the structural differences of agonist and antagonist binding. In this work, we have developed a new ensemble docking-based virtual screening protocol utilizing both agonist and antagonist bound S1R structures. This protocol was used to screen our in-house compound library. The S1R binding affinities of the 40 highest ranked compounds were measured in competitive radioligand binding assays and the sigma-2 receptor (S2R) affinities of the best S1R binders were also determined. This way three novel high affinity S1R ligands were identified and one of them exhibited a notable S1R/S2R selectivity.

Background(-)-Pentazocine has been hypothesized to induce analgesia via the κ-opioid (KOP) receptor, although the involvement of other opioid receptor subtypes in the effects of pentazocine remains unknown. In this study, we investigated the role of the μ-opioid (MOP) receptor in thermal, mechanical, and chemical antinociception induced by (-)-pentazocine using MOP receptor knockout (MOP-KO) mice.Results(-)-Pentazocine-induced thermal antinociception, assessed by the hot-plate and tail-flick tests, was significantly reduced in heterozygous and abolished in homozygous MOP-KO mice compared with wildtype mice. The results obtained from the (-)-pentazocine-induced mechanical and somatic chemical antinociception experiments, which used the hind-paw pressure and formalin tests, were similar to the results obtained from the thermal antinociception experiments in these mice. However, (-)-pentazocine retained its ability to induce significant visceral chemical antinociception, assessed by the writhing test, in homozygous MOP-KO mice, an effect that was completely blocked by pretreatment with nor-binaltorphimine, a KOP receptor antagonist. In vitro binding and cyclic adenosine monophosphate assays showed that (-)-pentazocine possessed higher affinity for KOP and MOP receptors than for δ-opioid receptors.ConclusionsThe present study demonstrated the abolition of the thermal, mechanical, and somatic chemical antinociceptive effects of (-)-pentazocine and retention of the visceral chemical antinociceptive effects of (-)-pentazocine in MOP-KO mice. These results suggest that the MOP receptor plays a pivotal role in thermal, mechanical, and somatic chemical antinociception induced by (-)-pentazocine, whereas the KOP receptor is involved in visceral chemical antinociception induced by (-)-pentazocine.

RationaleSerotonin syndrome (SS) is a potentially life-threatening condition characterized by autonomic and muscular hyperactivity resulting from the use of serotonergic drugs that bind to peripheral or central postsynaptic serotonin receptors. This syndrome can be easily confused with other clinical conditions, leading to delays in diagnosis and jeopardizing vital prognosis. Linezolid is utilized in the clinical management of gram-positive coccal infections, while pentazocine, an opioid analgesic, is frequently employed for pain relief in trauma patients. Currently, there are limited reports documenting the occurrence of SS associated with linezolid and pentazocine. In this report, we present the case of a 32-year-old man who developed SS following simultaneous administration of linezolid and pentazocine; his symptoms were effectively managed upon discontinuation of these medications.Patient concernsA 32-year-old male patient was treated with pentazocine and linezolid for pain management related to trauma as well as for a gram-positive coccal infection. One hour after administration, he exhibited tremors in his right limb along with hand tremors, profuse sweating, and sinus tachycardia; his body temperature subsequently rose to 40°C. Laboratory tests including white blood cell count, procalcitonin levels, and C-reactive protein, showed no significant changes compared to previous results. A follow-up computed tomography scan of the head revealed no new ischemic lesions.DiagnosesThe patient's physical examination, vital signs, and laboratory results were consistent with SS.InterventionsLinezolid and pentazocine were discontinued immediately. Midazolam (3-6 µg/kg/h) and dexmedetomidine (0.1-0.3 µg/kg/h) were administered, and oral diazepam (2.5 mg 3 times daily) was gradually continued.OutcomesFollowing this treatment regimen, the patient's profuse sweating improved significantly, and he became stable overall; his body temperature gradually returned to normal levels. Subsequently, the patient was transferred from the surgical intensive care unit to a general ward after 7 days of treatment.LessonsAlthough SS is not very common in patients using pentazocine and linezolid separately, it is important because it is an emergency condition that can result in death if not treated appropriately. This clinical case highlights the importance of thoroughly understanding the clinical manifestations of SS to ensure early and appropriate treatment management.