(3S,4R)-4-Thiophen-3-ylpyrrolidine-3-carboxylic acid hydrochloride

Rationale: Tramadol (1RS, 2RS)-2-[(dimethylamino)-methyl]-1-(3-methoxyphenyl)-cyclohexanol) is an atypical centrally acting analgesic agent with weak opioid receptor affinity that, like some antidepressants, enhances the extraneuronal concentrations of the monoamine neurotransmitters, noradrenaline and serotonin, by interfering with their re-uptake and release mechanisms. Objectives: The present study was undertaken to evaluate the potential role of 5-HT(1A) receptors and opioids receptors in the analgesic effect of tramadol in neuropathic pain. With this aim, the effect of either a selective 5-HT(1A) receptor antagonist (WAY-100635, N-2-[4-(2-methoxyphenyl-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane carboxamide) or a selective 5-HT(1A) receptor agonist (8-OH-DPAT, 8-hydroxy-2-(di-n-propylamine) tetralin hydrobromide) or an opioid receptor antagonist (naloxone; naloxone hydrochloride dihydrate) was investigated in combination with tramadol by means of the cold-plate test in the chronic constriction injury model in rats. Results: The results showed that WAY-100635 (0.8 mg/kg) significantly enhanced the antiallodynic effect of non-effective doses of tramadol (5-10 mg/kg). In contrast, 8-OH-DPAT (0.5 mg/kg) counteracted the antiallodynic effect of an effective dose of tramadol (22 mg/kg). Naloxone (0.5 mg/kg) partially counteracted the antiallodynic effect of tramadol (22 mg/kg). Conclusions: These findings suggest the involvement of opioid and 5-HT(1A) receptors in the antinociceptive effect of tramadol and support the idea that the combination of tramadol with compounds having 5-HT(1A) antagonist properties could be a new strategy to improve tramadol-induced analgesia in neuropathic pain.

Introduction: Despite a number of medicinally important pharmacological effects, the therapeutic use of psychostimulants is limited because of abuse potential and psychosis following long term use. Development of pharmacological agents for improving and extending therapeutic use of psychostimulants in narcolepsy, attention deficit hyperactivity disorder, Parkinson's disease, obesity and as cognitive enhancer is an important research imperative. In this regard, one potential target system is the 5-hydroxytryptamine (5-HT; serotonin) neurotransmitter system. The focus of the present article is to evaluate a potential role of 5-HT-1A receptor in the alleviation of abuse potential and psychosis-induced by prescription psychostimulants amphetamines and apomorphine. Method: Synaptic contacts between dopamine systems and 5-HT-1A receptors are traced. Studies on serotonin-1A influences on the modulation of dopamine neurotransmission and psychostimulant-induced behavioral sensitization are accumulated. Results: Inhibition of amphetamine and apomorphine-induced behavioral sensitization by co administration of 5-HT-1A agonists cannot be explained in terms of direct activation of 5-HT-1A receptors, because activation of pre- as well as postsynaptic 5-HT-1A receptors tends to increase dopamine neurotransmission. Conclusion: Long term use of amphetamine and apomorphine produces adaptive changes in 5-HT-1A receptor mediated functions, which are prevented by the co-use of 5-HT-1A agonists. In view of extending medicinal use of psychostimulants, it is important to evaluate the effects of co-use of 5-HT-1A agonists on potential therapeutic profile of amphetamine and apomorphine in preclinical research. It is also important to evaluate the functional significance of 5-HT-1A receptors on psychostimulant-induced behaviors in other addiction models such as drug self-administration and reinstatement of drug seeking behavior.

Stimulation of opioid receptors is widely used for relieving cancer pain in patients with advanced cancer. The expression of tissue opioid receptors varies depending on the types of cancer and it is regulated by several factors. This review provides a focused overview of the current evidence for the role of opioid receptors in modulating cancer progression, a discussion of the proposed underlying mechanisms and the pharmacological activity of opioid agonists and antagonists. Conflicting evidence from preclinical and clinical studies suggests the possible involvement of opioid receptor agonists in both the development and suppression of human cancer. Some retrospective clinical studies also show a possible detrimental effect on long-term patient outcomes. Among the opioid receptor agonists, morphine has been extensively studied in various cancer types. Moreover, various pathological processes of human cancer are affected by opioid receptor agonists, such as tumour growth, angiogenesis and immunosuppression. These findings highlight the functional value of opioid receptors in human cancer, and a potential double role of opioid receptor agonists and antagonists in human cancer treatment.