ABSTRACT
We examined the involvement of cytosolic calcium in the modulation of the formalin-induced nociceptive response by diabetes. Injection of formalin into the hindpaw of mice produced a biphasic nociceptive response consisting of immediate (first phase) and tonic (second phase) components. Although the duration of the first-phase response was significantly longer in diabetic mice than in non-diabetic mice, the second phase was significantly shorter in diabetic mice. The first-phase response was dose-dependently and significantly reduced by pretreatment with ryanodine, which blocks Ca(2+) release from Ca(2+)/caffeine-sensitive microsomal pools. The second-phase response was also significantly increased when diabetic mice were pretreated with ryanodine. However, ryanodine had no significant effect on either the first-phase or second-phase response in non-diabetic mice. On the other hand, pretreatment with thapsigargin, which inhibits Ca(2+) uptake into the inositol-1,4, 5-trisphosphate-sensitive microsomal Ca(2+) pool, significantly enhanced the first-phase response in non-diabetic mice. Furthermore, thapsigargin significantly and dose-dependently reduced the second phase of the formalin-induced nociceptive response in non-diabetic mice. Thapsigargin administered i.t. did not significantly affect either the first- or the second-phase response in diabetic mice. These results suggest that the change in the formalin-induced nociceptive response in diabetic mice may be due, at least in part, to the modification of nociceptive transmission in the spinal cord by intracellular calcium.
Subject(s)
Calcium/metabolism , Diabetic Neuropathies/metabolism , Nociceptors/metabolism , Animals , Diabetes Mellitus, Experimental/metabolism , Disinfectants , Enzyme Inhibitors/pharmacology , Formaldehyde , Injections, Spinal , Male , Mice , Mice, Inbred ICR , Neurons, Afferent/drug effects , Neurons, Afferent/metabolism , Nociceptors/drug effects , Ryanodine/pharmacology , Thapsigargin/pharmacologyABSTRACT
To investigate the role of protein kinase C in the attenuation of bradykinin-induced thermal hyperalgesia in diabetic mice, we examined the effects of a protein kinase C activator or inhibitor on the i.t. bradykinin-induced hyperalgesia in diabetic and non-diabetic mice. Intrathecal injection of bradykinin caused a transient antinociceptive effect, which diminished within 30 min, and then produced a thermal hyperalgesia, which lasted about 120 min, in non-diabetic mice. Although the duration of the antinociceptive phase was longer in diabetic mice than in non-diabetic mice, the hyperalgesic response was not observed in diabetic mice. The bradykinin-induced hyperalgesia was dose-dependently and significantly enhanced by pretreatment with calphostin C (0.3 to 3 pmol, i.t.), a specific protein kinase C inhibitor, in diabetic mice. However, calphostin C (3 pmol, i.t.) had no significant effect on bradykinin-induced hyperalgesia in non-diabetic mice. On the other hand, pretreatment with phorbol-12, 13-dibutyrate (12.5 to 50 pmol, i.t.), a protein kinase C activator, significantly and dose-dependently reduced bradykinin-induced hyperalgesia in non-diabetic mice. However, phorbol-12, 13-dibutyrate (50 pmol, i.t. ) had no significant effect on bradykinin-induced hyperalgesia in diabetic mice. These results suggest that the change in bradykinin-induced thermal hyperalgesia in diabetic mice may be due, at least in part, to the modification of nociceptive transmission in the spinal cord by the activation of protein kinase C.
Subject(s)
Bradykinin , Diabetes Mellitus, Experimental/physiopathology , Hyperalgesia/chemically induced , Hyperalgesia/physiopathology , Protein Kinase C/physiology , Animals , Bradykinin/analogs & derivatives , Bradykinin/pharmacology , Diabetes Mellitus, Experimental/enzymology , Enzyme Activators/pharmacology , Enzyme Inhibitors/pharmacology , Hot Temperature , Injections, Spinal , Male , Mice , Mice, Inbred ICR , Naphthalenes/pharmacology , Phorbol 12,13-Dibutyrate/pharmacology , Protein Kinase C/antagonists & inhibitors , Reaction Time/drug effectsABSTRACT
To clarify the possible mechanism of the antinociceptive effect of mexiletine, the effects of the agent on formalin- and algogenic mediator-induced nociceptive responses were examined as compared to lidocaine. Subcutaneous (s.c.) injection of 0.5% formalin into the hindpaw caused an acute nociceptive response that lasted about 5 min (first phase). This response then disappeared completely for about 5 min and then recurred lasting about 20 min (second phase). Intraperitoneal (i.p.) administration of mexiletine (10 and 30 mg/kg) significantly and dose-dependently reduced the durations of the first and second phases of formalin-induced nociceptive response. On the other hand, although i.p. administration of lidocaine (10 and 30 mg/kg) had no significant effect on the first phase of formalin-induced nociceptive response, the duration of the second phase response was significantly and dose-dependently reduced. Pretreatment with mexiletine resulted in a significant and dose-dependent inhibition of the nociceptive response produced by intrathecal (i.t.) injection of substance P (0.1 nM), somatostatin (1.0 nM), bradykinin (1 microgram/mouse) and prostaglandin (PG) F2 alpha (1 microgram/mouse). Although lidocaine had no significant effect on the substance P- or somatostatin-induced nociceptive response, bradykinin- and PGF2 alpha-induced nociceptive responses were inhibited. These results suggest that the antinociceptive effect of mexiletine involves the inhibition of substance P-, somatostatin-, bradykinin- and PGF2 alpha-mediated nociceptive transmission in the spinal cord. Furthermore, it is possible that the weaker antinociceptive effect of lidocaine as compared with that of mexiletine may be due to the lack of its inhibitory effect on substance P- and somatostatin-mediated nociceptive transmission in the spinal cord.
Subject(s)
Analgesics/pharmacology , Mexiletine/pharmacology , Nociceptors/drug effects , Pain/drug therapy , Anesthetics, Local/pharmacology , Animals , Bradykinin/toxicity , Dinoprostone/toxicity , Lidocaine/pharmacology , Male , Mice , Mice, Inbred ICR , Pain/chemically induced , Pain Measurement/drug effects , Somatostatin/toxicity , Substance P/toxicityABSTRACT
The duration of the somatostatin-, bradykinin- or prostaglandin F2alpha-induced nociceptive response was significantly less in diabetic mice than in non-diabetic mice. Subcutaneous injection of 7-benzylidenenaltrexone (0.1, 0.3 and 1 mg/kg), an antagonist of delta1-opioid receptors, had no significant effect on either somatostatin-, bradykinin- or prostaglandin F2alpha-induced nociceptive responses in non-diabetic mice. 7-Benzylidenenaltrexone (0.1 and 0.3 mg/kg, s.c.) also had no significant effect on somatostatin- or prostaglandin F2alpha-induced nociceptive responses in diabetic mice. However, the bradykinin-induced nociceptive response in diabetic mice was dose-dependently and significantly increased when 7-benzylidenenaltrexone (0.1, 0.3 and 1 mg/kg, s.c.) was injected 10 min before the injection of bradykinin. These results suggest that a spinal delta1-opioid receptor-mediated endogenous antinociceptive system may inhibit the bradykinin-mediated nociceptive responses in the second phase of the formalin-induced nociceptive response in diabetic mice.
Subject(s)
Benzylidene Compounds/therapeutic use , Diabetes Mellitus, Experimental/physiopathology , Naltrexone/analogs & derivatives , Narcotic Antagonists/therapeutic use , Pain/drug therapy , Receptors, Opioid, delta/drug effects , Animals , Bradykinin , Dinoprost , Dose-Response Relationship, Drug , Formaldehyde , Injections, Subcutaneous , Male , Mice , Mice, Inbred ICR , Naltrexone/therapeutic use , Pain/chemically induced , Receptors, Opioid, delta/antagonists & inhibitors , SomatostatinABSTRACT
Injection of formalin into the hindpaw of mice produced a biphasic nociceptive response consisting of immediate (first-phase) and tonic (second-phase) components. In diabetic mice, the flinching response of the first phase was increased while that in the second phase was decreased in diabetic mice relative to the results in non-diabetic mice. To examine the role of supraspinal and/or spinal endogenous delta1-opioid receptors in inhibiting the formalin-induced nociceptive response in diabetic mice, we assessed the effect of 7-benzylidenenaltrexone, a selective delta1-opioid receptor antagonist, and naltriben, a selective delta2-opioid receptor antagonist, administered either i.c.v. or i.t., on the formalin-induced flinching response. The second-phase response appeared when diabetic mice were pretreated with 7-benzylidenenaltrexone (0.1 and 0.3 mg/kg, s.c.), but not with naltriben (0.3 and 1 mg/kg, s.c.). On the other hand, while 7-benzylidenenaltrexone (0.1, 0.3 and 1 microg/mouse) administered i.t. had no significant effect on the first phase, it significantly and dose-dependently increased the second phase of the formalin-induced flinching response in diabetic mice. 7-Benzylidenenaltrexone (1 and 3 microg/mouse) administered i.c.v. had no significant effect on either the first- or the second-phase response in both non-diabetic and diabetic mice. These results suggest that a spinal delta1-opioid receptor-mediated endogenous antinociceptive system may inhibit the formalin-induced second phase of the nociceptive response in diabetic mice.
Subject(s)
Analgesics/pharmacology , Diabetes Mellitus, Experimental/physiopathology , Receptors, Opioid, delta/drug effects , Spinal Cord/drug effects , Animals , Benzylidene Compounds/administration & dosage , Benzylidene Compounds/pharmacology , Dose-Response Relationship, Drug , Formaldehyde , Injections, Intraventricular , Injections, Spinal , Injections, Subcutaneous , Male , Mice , Mice, Inbred ICR , Naltrexone/administration & dosage , Naltrexone/analogs & derivatives , Naltrexone/pharmacology , Narcotic Antagonists/pharmacology , Pain Measurement/drug effectsABSTRACT
We assessed the effect of naloxonazine, a selective mu 1-opioid receptor antagonist, on antinociception produced by intrathecal or intracerebroventricular injections of morphine in streptozotocin-induced diabetic mice. The antinociceptive effect of morphine (10 micrograms), administered i.c.v., was significantly less in diabetic mice than in non-diabetic mice. The antinociceptive effect of i.c.v. morphine was significantly reduced in both diabetic and non-diabetic mice following pretreatment with naloxonazine. There were no significant differences in the antinociceptive effect of morphine (1 microgram, i.t.) in diabetic and non-diabetic mice. Furthermore, naloxonazine had no significant effect on the antinociceptive effect of i.t. morphine in either diabetic or non-diabetic mice. On the other hand, the antinociceptive effects of i.c.v. and i.t. morphine were significantly reduced following pretreatment with beta-funaltrexamine, a selective mu-opioid receptor antagonist, in both diabetic and non-diabetic mice. In conclusion, mice with diabetes are selectively hyporesponsive to supraspinal mu 1-opioid receptor-mediated antinociception, but are normally responsive to activation of spinal mu 2-opioid receptors.
Subject(s)
Analgesics/pharmacology , Diabetes Mellitus, Experimental/physiopathology , Pain/physiopathology , Receptors, Opioid, mu/physiology , Animals , Injections, Intraventricular , Injections, Spinal , Male , Mice , Mice, Inbred ICR , Morphine/administration & dosage , Morphine/pharmacology , Naloxone/analogs & derivatives , Naloxone/pharmacology , Naltrexone/analogs & derivatives , Naltrexone/pharmacology , Narcotic Antagonists/pharmacology , Pain Measurement/drug effects , Receptors, Opioid, mu/antagonists & inhibitors , Spinal Cord/drug effects , Spinal Cord/metabolismABSTRACT
The involvement of delta-opioid receptor subtypes in cold water swim stress (CWSS)-induced antinociception in diabetic mice was compared with that in non-diabetic mice. Three-minute swim stress produced significant antinociception in both diabetic and non-diabetic mice as determined by the tail-pinch test. However, the extent of CWSS-induced antinociception in diabetic mice was significantly greater than that in non-diabetic mice. Pretreatment with naltriben, a selective delta 2-opioid receptor antagonist, significantly attenuated CWSS-induced antinociception in both non-diabetic and diabetic mice. In contrast, although 7-benzylidenenaltrexone, a selective delta 1-opioid receptor antagonist, significantly attenuated CWSS-induced antinociception in diabetic mice, it had no effect in non-diabetic mice. These results suggest that CWSS-induced antinociception in non-diabetic mice is mediated by delta 2-opioid receptors, whereas CWSS-induced antinociception in diabetic mice is mediated by both delta 1- and delta 2-opioid receptors. Furthermore, the enhanced CWSS-induced antinociception in diabetic mice may be due to the activation of delta 1-opioid receptors.
Subject(s)
Analgesia , Diabetes Mellitus, Experimental/physiopathology , Receptors, Opioid, delta/physiology , Stress, Physiological/physiopathology , Animals , Benzylidene Compounds/pharmacology , Cold Temperature , Male , Mice , Mice, Inbred ICR , Naltrexone/analogs & derivatives , Naltrexone/pharmacology , Streptozocin , SwimmingABSTRACT
1. We examined the effect of spirapril, a potent angiotensin converting enzyme (ACE) inhibitor, on the number of capsaicin-induced coughs in rats and compared with that of enalapril. 2. Chronic treatment with enalapril, at doses of 1 and 3 mg/kg, p.o., significantly and dose-dependently enhanced the number of capsaicin-induced coughs. 3. Chronic treatment with higher dose of spirapril (3 mg/kg, p.o.) also significantly enhanced the number of capsaicin-induced coughs. However, lower dose (1 mg/kg, p.o.) of spirapril had no significant effect on the number of capsaicin-induced coughs. 4. These results suggest that cough induced activity, one of the most serious side effects associated with chronic treatment with ACE inhibitors, of spirapril is relatively lower than that of enalapril.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Cough/chemically induced , Enalapril/analogs & derivatives , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Animals , Blood Pressure/drug effects , Cough/physiopathology , Enalapril/administration & dosage , Enalapril/pharmacology , Injections, Intravenous , Male , Rats , Rats, Sprague-Dawley , Reflex/drug effectsABSTRACT
We examined whether streptozotocin-induced diabetes can modulate beta-endorphin-induced antinociception in mice. While beta-endorphin administered i.c.v. produced a dose-dependent inhibition of the tail-flick response in both diabetic and non-diabetic mice, the antinociceptive response was greater in diabetic mice than in non-diabetic mice. The ED50 value of beta-endorphin administered i.c.v. in diabetic mice was significantly lower than that in non-diabetic mice. The antinociceptive effects of beta-endorphin administered i.c.v. in both diabetic and non-diabetic mice were significantly antagonized by s.c. administration of naltrindole, a selective delta-opioid receptor antagonist. beta-Endorphin administered i.t. also produced a dose-dependent antinociception in both diabetic and non-diabetic mice. However, the ED50 value of kappa-opioid receptor antagonist. On the other hand, the antinociceptive potency of DPDPE, a selective delta-opioid agonist, administered i.t. is significantly increased in diabetic mice, as compared with non-diabetic mice, whereas, the antinociceptive potency of U-50,488H, a kappa-opioid receptor agonist, administered i.t. is significantly less than in non-diabetic mice. These results suggest that diabetes may modulate beta-endorphin-induced antinociception differently at the spinal and supraspinal levels.
Subject(s)
Analgesics/pharmacology , Cerebral Ventricles/drug effects , Diabetes Mellitus, Experimental/physiopathology , Naltrexone/analogs & derivatives , Narcotic Antagonists/pharmacology , Pain/prevention & control , beta-Endorphin/pharmacology , 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer , Animals , Cerebral Ventricles/physiology , Cerebral Ventricles/physiopathology , Dose-Response Relationship, Drug , Enkephalin, Ala(2)-MePhe(4)-Gly(5)- , Enkephalin, D-Penicillamine (2,5)- , Enkephalins/pharmacology , Injections, Intraventricular , Male , Mice , Mice, Inbred ICR , Naltrexone/administration & dosage , Naltrexone/pharmacology , Pain/physiopathology , Pyrrolidines/pharmacology , Reference Values , beta-Endorphin/administration & dosageABSTRACT
We investigated the effect of mexiletine on the formalin-induced nociceptive response and its modulation by diabetes. We also investigated the effects of mexiletine on intrathecally-administered substance P- and somatostatin-induced nociceptive responses in both non-diabetic and diabetic mice. Intraperitoneal injection of mexiletine (30 mg/kg) significantly reduced the duration of the formalin-induced nociceptive response in both non-diabetic and diabetic mice. When mexiletine (30 mg/kg, i.p.) was injected 30 min before injection of substance P (SP), it significantly inhibited SP-induced nociceptive responses in both non-diabetic and diabetic mice. Furthermore, mexiletine also significantly inhibited the intensity of somatostatin (SST)-induced antinociceptive effect of mexiletine in diabetic mice involves the inhibition of SP- and SST-mediated nociceptive transmission in the spinal cord.
Subject(s)
Mexiletine/pharmacology , Pain/prevention & control , Animals , Diabetes Mellitus, Experimental/physiopathology , Formaldehyde , Injections, Intraperitoneal , Injections, Spinal , Male , Mice , Mice, Inbred ICR , Nociceptors/drug effects , Pain/chemically induced , Pain/physiopathology , Somatostatin/administration & dosage , Somatostatin/antagonists & inhibitors , Streptozocin , Substance P/administration & dosage , Substance P/antagonists & inhibitorsABSTRACT
Intrathecal administration of endothelin-1 (ET-1) produced dose-dependent antinociceptive effects in the tail-flick test. The antinociceptive effects of ET-1 were attenuated significantly by pretreatment with naloxone and the delta receptor-selective antagonist naltrindole. The antinociceptive effects of ET-1 were also significantly attenuated by pretreatment with verapamil, an L-type Ca(2+)-channel blocker. These results suggest that the mechanism underlying the antinociceptive effects of ET-1 involves mediation, at least in part, by Ca(2+)-induced release of endogenous opioids, which act on delta-opioid receptors.
Subject(s)
Endothelins/pharmacology , Nociceptors/drug effects , Animals , Endothelins/antagonists & inhibitors , Hot Temperature , Injections, Spinal , Male , Mice , Mice, Inbred ICR , Pain Measurement , Time Factors , Verapamil/pharmacologyABSTRACT
Intrathecal administration of endothelin-1 (ET-1) produced a dose-dependent increase in tail-pinch latency, i.e., antinociception, in both diabetic and non-diabetic mice. The dose ranges which produced a significant antinociception in diabetic mice (0.0001 to 0.0003 nmol) were lower than those in non-diabetic mice (0.001 to 0.003 nmol). Furthermore, the antinociceptive effect of ET-1 in diabetic mice was decreased when the doses of ET-1 were increased. Indeed, when ET-1 in a dose of 0.003 nmol, which produced significant antinociception in non-diabetic mice, it had no antinociceptive effect in diabetic mice. These results suggest that the mechanism which underlies the antinociceptive effects of ET-1 is up-regulated in diabetic mice, as compared with that in non-diabetic mice.
Subject(s)
Diabetes Mellitus, Experimental/physiopathology , Endothelins/pharmacology , Nociceptors/drug effects , Pain/physiopathology , Animals , Injections, Spinal , Male , Mice , Mice, Inbred ICR , Pain Measurement , StreptozocinABSTRACT
In non-diabetic mice, s.c. injection of formalin to the hindpaw had a biphasic effect: an immediate nociceptive response (first-phase) followed by a tonic response (second-phase). However, only the immediate nociceptive response was observed in diabetic mice. The duration of the first-phase response was significantly longer in diabetic mice than in non-diabetic mice. In diabetic mice, when spantide, an antagonist of substance P, reduced the duration of the nociceptive response in the first-phase to the levels that were observed in non-diabetic mice, the second-phase response appeared. The second phase also became apparent in diabetic mice after pretreatment with naltrindole (3 mg/kg), an antagonist of delta-opioid receptors. These results suggest that a negative control system, which is mediated by delta-opioid receptors and links substance P with somatostatin-mediated nociceptive transmission, may inhibit the formalin-induced second-phase of the nociceptive response in diabetic mice.
Subject(s)
Diabetes Mellitus, Experimental/metabolism , Formaldehyde/pharmacology , Nociceptors/drug effects , Analgesics/administration & dosage , Analgesics/pharmacology , Animals , Behavior, Animal/drug effects , Diabetes Mellitus, Experimental/drug therapy , Dose-Response Relationship, Drug , Injections, Spinal , Male , Mice , Mice, Inbred ICR , Naltrexone/administration & dosage , Naltrexone/analogs & derivatives , Naltrexone/pharmacology , Narcotic Antagonists/administration & dosage , Narcotic Antagonists/pharmacology , Receptors, Opioid, delta/drug effects , Substance P/administration & dosage , Substance P/analogs & derivatives , Substance P/pharmacologyABSTRACT
The effects of cold water swim stress (CWSS) on the nociceptive responses to i.t. administered substance P (SP) and somatostatin (SST) were examined. Male ICR mice, weighing about 30 g, were forced to swim in water at 20 degrees C for 3 min. In unstressed mice, i.t. injection of SP (0.1 nmol) and SST (1 nmol), respectively, produced nociceptive-related behaviors. Although CWSS had no effect on the intensity of the SP-induced nociceptive responses, CWSS significantly reduced the intensity of the SST-induced nociceptive responses. The effect of CWSS on the SST-induced nociceptive responses was blocked by naloxone (5 mg/kg, s.c.) and naltrindole (1 mg/kg, s.c.), a selective delta-opioid receptor antagonist, but not by beta-funaltrexamine (20 mg/kg, s.c.), a selective mu-opioid receptor antagonist. These results indicate that CWSS may selectively reduce the SST-induced nociceptive responses primarily through delta-opioid receptors.
Subject(s)
Pain/physiopathology , Somatostatin/administration & dosage , Stress, Physiological/physiopathology , Substance P/administration & dosage , Animals , Cold Temperature , Male , Mice , Mice, Inbred ICR , Naloxone/pharmacology , Receptors, Opioid, delta/physiology , SwimmingABSTRACT
Male ICR mice were rendered diabetic by i.v. injection of streptozotocin. The nociceptive behavioral responses to i.t. injection of somatostatin (SST) but nor substance P (SP) were attenuated in diabetic mice compared with that in non-diabetic mice. Spantide, a SP receptor antagonist, enhanced the nociceptive response induced by i.t. SST in diabetic mice. Pretreatment of mice with SP reduced the SST-induced nociceptive response in non-diabetic mice. These results suggest that a endogenous antinociceptive system may exist which links SP with SST-mediated nociceptive transmission in the spinal cord. Furthermore, this endogenous antinociceptive system may be enhanced in diabetic mice.
Subject(s)
Diabetes Mellitus, Experimental/physiopathology , Motor Activity/drug effects , Pain/chemically induced , Somatostatin/pharmacology , Substance P/pharmacology , Animals , Injections, Spinal , Male , Mice , Mice, Inbred ICR , Pain Measurement/drug effects , Pain Threshold/drug effects , Somatostatin/administration & dosage , Substance P/administration & dosageABSTRACT
Forced swimming stress-induced antinociception (FSSIA) was assessed using the formalin test. Male ICR mice, weighing about 30 g, were forced to swim in water at 20 degrees C for 3 min. In unstressed mice, SC injection of formalin (0.5%) to the hindpaw caused a biphasic response: an immediate nociceptive response (first phase) followed by a tonic response (second phase). Although forced swimming stress (FSS) had no effect on the duration of the first-phase response, FSS significantly reduced the duration of the second-phase response. The effect of FSSIA on the second-phase response was blocked by naltrindole (1 mg/kg, SC), a selective delta-opioid receptor antagonist, but not by beta-funaltrexamine (20 mg/kg, SC), a selective mu-opioid receptor antagonist. These results indicate that FSS may selectively reduce the second phase of the formalin-induced nociceptive response, primarily through delta-opioid receptors.
Subject(s)
Nociceptors/physiology , Receptors, Opioid, delta/physiology , Stress, Psychological/physiopathology , Animals , Formaldehyde , Male , Mice , Mice, Inbred ICR , Naltrexone/analogs & derivatives , Naltrexone/pharmacology , Narcotic Antagonists/pharmacology , Nociceptors/drug effects , Pain Measurement/drug effects , Receptors, Opioid, delta/agonists , Receptors, Opioid, delta/antagonists & inhibitors , Stress, Psychological/psychology , SwimmingABSTRACT
The effects of selective sigma-ligands on the capsaicin-induced cough reflex in rats were studied. Intraperitoneal injection of (+)-N-allylnormetazocine ((+)-SKF-10,047) and N,N'-di(ortho-tolyl)guanidine (DTG) in doses that ranged from 0.3 to 3.0 mg/kg decreased the number of coughs dose dependently. The antitussive effects of these sigma-ligands were significantly attenuated by pretreatment with haloperidol. Pretreatment with haloperidol also markedly reduced the antitussive effects of (+/-)-pentazocine and dextromethorphan. These results suggest that haloperidol-sensitive sigma-sites may be involved in the regulation of coughs.
Subject(s)
Antitussive Agents/pharmacology , Cough/drug therapy , Guanidines/pharmacology , Haloperidol/pharmacology , Phenazocine/analogs & derivatives , Receptors, sigma/drug effects , Animals , Capsaicin , Cough/chemically induced , Dose-Response Relationship, Drug , Drug Interactions , Injections, Intraperitoneal , Male , Phenazocine/administration & dosage , Phenazocine/pharmacology , Rats , Rats, Sprague-Dawley , StereoisomerismABSTRACT
The influence of diabetes on the effects of morphine on the responses of ventrobasal (VB) thalamic neurons to mechanical noxious stimuli were studied in chloral hydrate-anesthetized rats. Animals were rendered diabetic by an injection of streptozotocin (60 mg/kg, i.v.). Morphine (0.3 mg/kg), administered i.v., produced a reduction in the responsiveness of VB thalamic neurons to noxious stimulation in control rats. This effect was reversed by naloxone. In contrast, the inhibitory effects of morphine on the nociceptive responses of VB thalamic neurons were significantly attenuated in diabetic rats, as compared with the controls. However, there were no significant differences in inhibitory potency between diabetic and control rats when morphine (30 nM) was administered intrathecally. It seems likely that these changes in the sensitivity of VB thalamic neurons to morphine are, to some extent, the source of the reduction in the analgesic efficacy of morphine in diabetic rats.
Subject(s)
Diabetes Mellitus, Experimental/physiopathology , Morphine/pharmacology , Neurons/drug effects , Nociceptors/drug effects , Thalamic Nuclei/cytology , Animals , Glutamates/administration & dosage , Glutamates/pharmacology , Glutamic Acid , Injections, Intravenous , Injections, Spinal , Iontophoresis , Male , Morphine/administration & dosage , Rats , Rats, Sprague-Dawley , Thalamic Nuclei/drug effectsABSTRACT
We examined the effect of mexiletine on the threshold for pain perception as determined by the application of mechanical noxious stimuli (tail-pinch) in diabetic mice. Mexiletine produced a pronounced analgesic effect in diabetic mice in a dose-dependent manner. Mexiletine (10(-5)M) significantly inhibited the K(+)-evoked release of substance P from the slices of spinal cord of diabetic mice. These results suggest that the reduction of release of substance P from the nociceptive afferent terminal in the spinal cord is involved in the mechanisms of mexiletine analgesia in diabetic mice.