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162 STRUCTURE-BASED SELECTION OF ANTIDEPRESSANTS AND ANTICONVULSANTS FOR ANTIPRURITIC AND ANALGESIC THERAPY
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Poster Sessions / European Journal of Pain 13 (2009) S55–S285
determination of pain threshold by thermal irritation method (hot plate) at 55º C. Anticonvulsive activity has been studied by corazole spasm test. Activity has been calculated in percentage related to control group of animals. The tests have shown that all compounds have analgesic activity on the level within 78–137%. The highest effect is shown by carboxamide with p-nitrophenyl fragment (137%). 10-Camphorsulphonic acid derivatives had no anticonvulsive effect but they have shown significant analgesic action (136%). The greatest anticonvulsive activity has been shown by p-chlorophenyl(408%) and p-nitrophenyl (463%) sulphonamides. It is indicative that these compounds possess simultaneously another kind of neurotropic activity, in particular antihypoxic and tranquilizing one; this fact raises the value of developed preparates. The detection of correlation between chemical structure and biological activity in frame amine row defines an opportunity of the directed synthesis of new active neurotropic agents. 161 EXPRESSION OF EXTRACELLULAR-SIGNAL REGULATED KINASES IN MONOAMINERGIC BRAINSTEM NUCLEI OF NEUROPATHIC PAIN RATS SUBJECTED NOXIOUS STIMULATION AND ANTIDEPRESSANTS TREATMENT G. Borges1 *, E. Berrocoso2 , A. Ortega-Alvaro2 , J.A. Mico´ 2 , F. Neto1 . 1 Faculty of Medicine, University of Porto, Porto, Portugal; 2 Departamento de Neurociencias (Farmacolog´ıa y Psiquiatria), Grupo de Investigaci´ on y Dessarollo en Neuropsicofarmacolog´ıa, Facultad de Medicina, Universitad de C´ adiz, C´ adiz, Spain The mechanisms of antidepressants effects in neuropathic pain relief are not understood. Extracellular-signal regulated kinases (ERKs) are implicated in antidepressants effects and pain processing. We evaluated the effect of noxious stimulation and antidepressants administration on ERKs’ activation in the chronic constriction injury (CCI) model of neuropathic pain. SHAM-operated controls and CCI anaesthetised rats received mechanical stimulation (SHAM or CCI stimulated). Others did not receive stimulation (SHAM or CCI non-stimulated). Separate CCI or SHAM rats were treated for 21 days with saline or antidepressants (amitriptyline or duloxetine). Immunoreactivity against pERKs1/2 was analysed in brainstem nuclei. Baseline pERKs1/2 expression was observed in the A5, Locus Coeruleus (LC), Lateral Paragigantocellular (LPGi) and Lateral Reticular (LRt) nuclei of SHAM-Non-Stimulated and SHAM-Saline animals. CCI-Stimulated or CCI-Non-Stimulated showed increased pERKs in A5, LPGi and LRt, but decreased labelling intensity in LC. No changes were detected between stimulated and non-stimulated groups. Amitrityline and either amitrityline or duloxetine induced pERKs increases in A5 and LPGI, respectively, of SHAM rats. Among CCI rats, antidepressants had no effect on pERKs in any region but significant decreases were detected in CCI-amitriptyline compared to SHAM-amitriptyline rats, in A5 and in Dorsal Raphe. Neuropathic pain changed ERKs1/2 activation on some brainstem regions. Noxious stimulation had no effects. Antidepressants seem to act on ERKs pathway in monoaminergic regions under normal conditions. Under chronic painful input these mechanisms seem altered. Grant: PI070687, HP2006–0062, Spain; E-42/07, CRUP, Portugal. 162 STRUCTURE-BASED SELECTION OF ANTIDEPRESSANTS AND ANTICONVULSANTS FOR ANTIPRURITIC AND ANALGESIC THERAPY N.N. Shestakova1 *, I. Masalov1 , E. Tsvetkov1 , N. Vanchakova2 . 1 Sechenov Institute of Evolutionary Physiology and Biochemistry Russian Academy of Sciences, Saint-Petersburg, Russia; 2 The State Pavlov Medical University, Saint-Petersburg, Russia Background and aims: The 3D-structural criterion for selection of antidepressants and anticonvulsants for management of itch
and pain syndromes in patients with end-stage renal disease under chronic hemodialysis (ESRD) and patients with insulindependent diabetes (IDDM) has been formulated. The spatial group determining drug’s antipruritic and analgesic potencies consists of two centralized aromatic rings directed to each other at an angle of 120 degrees. The aim of the present investigation is to understand antipruritic and analgesic mechanisms of the selected effective drugs. Methods: Molecular structure analysis of drugs; whole-cell patch clamp technique; standard clinical and psychiatric investigations of randomized patient groups. Results: 55 drugs belonging to various classes of antidepressants and anticonvulsants have been studied. By modeling methods the drug molecules having defined structure have been obtained to form stable complexes with Na+ -ion. Forming Na+ -complex such molecules get a positive charge and additional physical and chemical properties. The electrophysiological experiments have shown that drugs having the group reduce peak amplitude of voltage-gated sodium current. Our clinical studies of 111 ESRDpatients and 186 IDDM-patients have revealed the high antipruritic and analgesic potency of selected by structural criterion drugs (mianserine, tianeptine and carbamazepine) considering of mental status and sex of patients, pain or itch prevalence. Conclusions: Irrespective of the base drug mechanisms the antipruritic and analgesic potency of drugs is correlated with drug structure, their ability to form stable Na+ -complexes and effect on voltage-gated sodium channels of neurons. 163 THE EFFECTS OF CITALOPRAM AND ESCITALOPRAM IN VISCERAL PAIN AND BEHAVIORAL MODELS IN MICE: EXPERIMENTAL RESEARCHES L. Tartau *. Pharmacology, Algesiology Department, Gr.T. Popa University of Medicine and Pharmacy, Iasi, Romania Citalopram and escitalopram are selective inhibitors of serotonin reuptake, with high affinity for the primary binding site on the serotonin transporter protein. Aim: Experimental researches on the effects of citalopram and escitalopram in a visceral pain and in a behavioral model in mice. Material and Method: The experiment was carried out, with white Swiss mice (20–25 g), distributed into 6 groups of 7 animals each, treated intraperitoneally for 14 days, as follows: Group I (Control): saline solution 0.3 ml; Group II (CIT 5): citalopram 5 mg/kbw; Group III (CIT 10): citalopram 10 mg/kbw; Group IV (ESCIT 25): escitalopram 25 mg/kbw; Group V (ESCIT 50): escitalopram 50 mg/kbw; Group VI (MOR): morphine 0.2 mg/kbw, subcutaneously administered in the last day. The test of colon chemical irritation with capsaicin was used as a visceral pain test. The antidepressants psycho-motor abilities were tested in the Activity Cage device, in order to investigate the both global motor behaviour and the number of escape attempts. ANOVA method, followed by Newman-Keuls, test were used for analysis of the data. Results: Citalopram induced dose dependent antinociception, 5 minutes after colon irritation, in capsaicin inflammation model, while escitalopram possesses no antinociceptive properties when injected i.p. In our experimental conditions both citalopram and escitalopram administered, do not significant influence the global motor behaviour in mice. Conclusions: In visceral pain model used, only citalopram exhibited significant antinociceptive effects in visceral pain model. The effects of were less intense than those of morphine.
Poster Sessions / European Journal of Pain 13 (2009) S55–S285
determination of pain threshold by thermal irritation method (hot plate) at 55º C. Anticonvulsive activity has been studied by corazole spasm test. Activity has been calculated in percentage related to control group of animals. The tests have shown that all compounds have analgesic activity on the level within 78–137%. The highest effect is shown by carboxamide with p-nitrophenyl fragment (137%). 10-Camphorsulphonic acid derivatives had no anticonvulsive effect but they have shown significant analgesic action (136%). The greatest anticonvulsive activity has been shown by p-chlorophenyl(408%) and p-nitrophenyl (463%) sulphonamides. It is indicative that these compounds possess simultaneously another kind of neurotropic activity, in particular antihypoxic and tranquilizing one; this fact raises the value of developed preparates. The detection of correlation between chemical structure and biological activity in frame amine row defines an opportunity of the directed synthesis of new active neurotropic agents. 161 EXPRESSION OF EXTRACELLULAR-SIGNAL REGULATED KINASES IN MONOAMINERGIC BRAINSTEM NUCLEI OF NEUROPATHIC PAIN RATS SUBJECTED NOXIOUS STIMULATION AND ANTIDEPRESSANTS TREATMENT G. Borges1 *, E. Berrocoso2 , A. Ortega-Alvaro2 , J.A. Mico´ 2 , F. Neto1 . 1 Faculty of Medicine, University of Porto, Porto, Portugal; 2 Departamento de Neurociencias (Farmacolog´ıa y Psiquiatria), Grupo de Investigaci´ on y Dessarollo en Neuropsicofarmacolog´ıa, Facultad de Medicina, Universitad de C´ adiz, C´ adiz, Spain The mechanisms of antidepressants effects in neuropathic pain relief are not understood. Extracellular-signal regulated kinases (ERKs) are implicated in antidepressants effects and pain processing. We evaluated the effect of noxious stimulation and antidepressants administration on ERKs’ activation in the chronic constriction injury (CCI) model of neuropathic pain. SHAM-operated controls and CCI anaesthetised rats received mechanical stimulation (SHAM or CCI stimulated). Others did not receive stimulation (SHAM or CCI non-stimulated). Separate CCI or SHAM rats were treated for 21 days with saline or antidepressants (amitriptyline or duloxetine). Immunoreactivity against pERKs1/2 was analysed in brainstem nuclei. Baseline pERKs1/2 expression was observed in the A5, Locus Coeruleus (LC), Lateral Paragigantocellular (LPGi) and Lateral Reticular (LRt) nuclei of SHAM-Non-Stimulated and SHAM-Saline animals. CCI-Stimulated or CCI-Non-Stimulated showed increased pERKs in A5, LPGi and LRt, but decreased labelling intensity in LC. No changes were detected between stimulated and non-stimulated groups. Amitrityline and either amitrityline or duloxetine induced pERKs increases in A5 and LPGI, respectively, of SHAM rats. Among CCI rats, antidepressants had no effect on pERKs in any region but significant decreases were detected in CCI-amitriptyline compared to SHAM-amitriptyline rats, in A5 and in Dorsal Raphe. Neuropathic pain changed ERKs1/2 activation on some brainstem regions. Noxious stimulation had no effects. Antidepressants seem to act on ERKs pathway in monoaminergic regions under normal conditions. Under chronic painful input these mechanisms seem altered. Grant: PI070687, HP2006–0062, Spain; E-42/07, CRUP, Portugal. 162 STRUCTURE-BASED SELECTION OF ANTIDEPRESSANTS AND ANTICONVULSANTS FOR ANTIPRURITIC AND ANALGESIC THERAPY N.N. Shestakova1 *, I. Masalov1 , E. Tsvetkov1 , N. Vanchakova2 . 1 Sechenov Institute of Evolutionary Physiology and Biochemistry Russian Academy of Sciences, Saint-Petersburg, Russia; 2 The State Pavlov Medical University, Saint-Petersburg, Russia Background and aims: The 3D-structural criterion for selection of antidepressants and anticonvulsants for management of itch
and pain syndromes in patients with end-stage renal disease under chronic hemodialysis (ESRD) and patients with insulindependent diabetes (IDDM) has been formulated. The spatial group determining drug’s antipruritic and analgesic potencies consists of two centralized aromatic rings directed to each other at an angle of 120 degrees. The aim of the present investigation is to understand antipruritic and analgesic mechanisms of the selected effective drugs. Methods: Molecular structure analysis of drugs; whole-cell patch clamp technique; standard clinical and psychiatric investigations of randomized patient groups. Results: 55 drugs belonging to various classes of antidepressants and anticonvulsants have been studied. By modeling methods the drug molecules having defined structure have been obtained to form stable complexes with Na+ -ion. Forming Na+ -complex such molecules get a positive charge and additional physical and chemical properties. The electrophysiological experiments have shown that drugs having the group reduce peak amplitude of voltage-gated sodium current. Our clinical studies of 111 ESRDpatients and 186 IDDM-patients have revealed the high antipruritic and analgesic potency of selected by structural criterion drugs (mianserine, tianeptine and carbamazepine) considering of mental status and sex of patients, pain or itch prevalence. Conclusions: Irrespective of the base drug mechanisms the antipruritic and analgesic potency of drugs is correlated with drug structure, their ability to form stable Na+ -complexes and effect on voltage-gated sodium channels of neurons. 163 THE EFFECTS OF CITALOPRAM AND ESCITALOPRAM IN VISCERAL PAIN AND BEHAVIORAL MODELS IN MICE: EXPERIMENTAL RESEARCHES L. Tartau *. Pharmacology, Algesiology Department, Gr.T. Popa University of Medicine and Pharmacy, Iasi, Romania Citalopram and escitalopram are selective inhibitors of serotonin reuptake, with high affinity for the primary binding site on the serotonin transporter protein. Aim: Experimental researches on the effects of citalopram and escitalopram in a visceral pain and in a behavioral model in mice. Material and Method: The experiment was carried out, with white Swiss mice (20–25 g), distributed into 6 groups of 7 animals each, treated intraperitoneally for 14 days, as follows: Group I (Control): saline solution 0.3 ml; Group II (CIT 5): citalopram 5 mg/kbw; Group III (CIT 10): citalopram 10 mg/kbw; Group IV (ESCIT 25): escitalopram 25 mg/kbw; Group V (ESCIT 50): escitalopram 50 mg/kbw; Group VI (MOR): morphine 0.2 mg/kbw, subcutaneously administered in the last day. The test of colon chemical irritation with capsaicin was used as a visceral pain test. The antidepressants psycho-motor abilities were tested in the Activity Cage device, in order to investigate the both global motor behaviour and the number of escape attempts. ANOVA method, followed by Newman-Keuls, test were used for analysis of the data. Results: Citalopram induced dose dependent antinociception, 5 minutes after colon irritation, in capsaicin inflammation model, while escitalopram possesses no antinociceptive properties when injected i.p. In our experimental conditions both citalopram and escitalopram administered, do not significant influence the global motor behaviour in mice. Conclusions: In visceral pain model used, only citalopram exhibited significant antinociceptive effects in visceral pain model. The effects of were less intense than those of morphine.