Relationship between analgesia and extracellular morphine in brain and spinal cord in awake rats

Extracellular concentrations of morphine from the dorsal spinal cord, the periaqueductal gray (PAG) including the dorsal raphé, and the lateral hypothalamus were measured by microdialysis in awake rats after intraperitoneal (i.p.) administration of 2.5, 5.0 and 10 mg/kg morphine. Morphine concentrations in all areas showed similar time courses: morphine was detected in the first dialysate sample (13-15 min) and maximal concentrations were reached at 45 min after injection. When in vivo recoveries of morphine from the spinal cord and brain areas were taken into account, no significant differences between morphine concentrations in the various areas were found. The relationship between extracellular morphine concentrations and morphine-induced analgesic behavior was investigated by simultaneously measuring morphine in the dialysate and its analgesic effect in the paw-withdrawal and tail-flick tests. In all areas sampled, the extracellular concentrations of morphine at different times after i.p. injection, significantly correlated with the magnitude of behavioral analgesia assessed by either test. The highest correlation was obtained between extracellular concentrations of morphine in the spinal cord and PAG and behavioral analgesia assessed in the paw-withdrawal test. Our data indicate that, after systemic injection, morphine is evenly distributed throughout the spinal cord and brain including potential anatomical sites of morphine's analgesic action. We estimate that the minimal extracellular morphine concentration in spinal cord that is required to produced a significant increase in nociceptive threshold is approximately 100 pg/25 microl, which corresponds to a tissue concentration of about 100 mg/g of morphine.     

Safety of Brucella abortus strain RB51 in Bison

We compared the efficacy of two clinically available drugs with N-methyl-D-aspartate receptor antagonist properties, dextromethorphan and ketamine, in potentiating morphine-induced antinociception. Ketamine alone at 0.3-3 mg/kg had no effect on the hot plate test and at 10 mg/kg caused sedation/motor deficits. The antinociceptive effect of 5 mg/kg morphine was slightly enhanced by 1 mg/kg, but not 0.3 or 3 mg/kg, ketamine. Dextromethorphan alone at 45 mg/kg had no effect, but at 60 mg/kg caused sedation/motor deficit. At 15-45 mg/kg, dextromethorphan significantly and dose-dependently increased the magnitude and duration of morphine-induced antinociception. Dextromethorphan also potentiated morphine at doses that, by themselves, did not cause antinociception (1-2 mg/kg). Implications: Dextromethorphan was more effective than ketamine in potentiating morphine-induced antinociception. Dextromethorphan may thus be the drug of choice for testing the interactions between N-methyl-D-aspartate antagonists and morphine clinically.     

Activation and expression of endogenous pain control mechanisms in rats given repeated nociceptive tests under the influence of naloxone.

In six experiments, it was found that animals administered the opiate receptor blocker naloxone prior to either hot-plate or tail-flick nociceptive tests developed reduced sensitivity to pain relative to animals tested under saline. The naloxone-induced analgesia was most pronounced following administration of 10 mg/kg naloxone, with weaker effects occurring at 0.5 and 2 mg/kg. The effect manifested itself in tests using mild (48.5° hot-plate tests), but not more severe (52° or 56° hot-plate tests), intensities of nociceptive stimulation. The analgesia observed in animals tested under naloxone arose in part from the attenuation of the habituation of stress-induced analgesia produced by the novelty of the test apparatus, and in part from exposure to nociceptive stimulation. It appears to be mediated by a nonopiate mechanism; naloxone enhanced the analgesia produced by exposure to brief, continuous shock, but blocked the analgesia elicited by prolonged, intermittent shock (see Lewis, Cannon, & Liebeskind, 1980). We also found that administration of naloxone prior to nociceptive testing enhanced the development of conditioned autoanalgesia (as assessed by nociceptive tests conducted under saline), and that the enhanced conditioned autoanalgesia summated with the analgesic effect of morphine. The results are discussed in terms of the activation and expression of both opiate and nonopiate pain suppression mechanisms; their implications for models of situation specific morphine analgesic tolerance are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Family history as a risk factor for ulcerative colitis-associated colon cancer in cotton-top tamarin

1. Debate exists as to the nature of antidepressant-induced antinociception. It is unclear whether antidepressants are inherently antinociceptive, are able to potentiate opioid antinociception or both. We have used the acetic acid induced abdominal constriction assay in mice to investigate antidepressant-induced antinociception. 2. All the antidepressants tested (s.c.) produced dose-dependent protection against acetic acid-induced abdominal constriction. Similarly, morphine and aspirin were also effective antinociceptive agents in this nociceptive assay. 3. Opioid antagonists, naloxone (0.5 mg kg(-1), s.c.) and naltrindole (1 mg kg(-1), s.c.), shifted the dose-response relationships to the right for each of the antidepressant agents (dothiepin, amitriptyline, sibutramine, (+)-oxaprotiline and paroxetine). In this context the naloxone dose-ratios were 1.95, 3.90, 2.32, 4.50 and 2.65, with naltrindole dose-ratios of 4.36, 17.00, 4.28, 11.48 and 2.65 were obtained, respectively. Naloxone also shifted the morphine dose-response relationship to the right, by a factor of 2.62, whilst naltrindole had no effect upon morphine antinociception. Aspirin antinociception remained unaffected by both opioid antagonists. 4. The enkephalin catabolism inhibitor acetorphan, by itself, produced no activity in this test at a dose of 10 mg kg(-1) (s.c.). However, at higher doses, acetorphan produced a linear dose-response relationship against acetic acid-induced abdominal constriction. 5. When acetorphan was administered before either the antidepressants or morphine, there was a clear potentiation of the antidepressant- or morphine-induced antinociception. However, acetorphan had no effect on aspirin antinociception. 6. Since neither of the opioid antagonists were able to attenuate, nor was acetorphan able to potentiate, aspirin antinociception, we concluded that the mechanism of antidepressant-induced antinociception is different from that of the non-steroidal anti-inflammatory drugs. 7. These data are consistent with the view that antidepressants may induce endogenous opioid peptide release, as shown by the acetorphan study. In this context, the ability of naltrindole to displace the antidepressant dose-response relationship to the right without affecting morphine antinociception, implicates the delta-opioid receptor and endogenous opioid peptides in antidepressant-induced antinociception.     

Partial loss of tolerance liability to morphine analgesia in mice lacking the nociceptin receptor gene

In mice lacking the nociceptin (or orphanin FQ) receptor gene, when 10 mg/kg of morphine was subcutaneously given, a potent analgesia in the tail pinch test was observed. The analgesic effect of morphine was equivalent among wild-type, heterozygous and homozygous mutant mice. When morphine was given to such mice in a dose of 10 mg/kg once per day for 5 days, wild-type and heterozygous mice showed marked tolerance or reduction in the morphine analgesia on the 5th day, while homozygous mice showed only 50% reduction in the peripheral analgesia of morphine. These findings suggest that nociceptin or its receptor plays important roles in the in vivo mechanism for the development of morphine tolerance.     

Comparison of the fatty acid compositions in intraepithelial and infiltrating lesions of the cervix: part II, free fatty acid profiles

Clinical studies report a low incidence of intestinal side effects with transdermally administered fentanyl (TTS-fentanyl) in comparison with oral morphine. To support these clinical data, analgesic and intestinal effects of both opioids were compared in rats. After subcutaneous injection, analgesia in the tail withdrawal reaction test was obtained at a peak effect dose of 0.032 mg/kg with fentanyl and 8.0 mg/kg with morphine. This analgesic dose exceeded the ED50 for inhibition of castor oil-induced diarrhea only slightly (1.1 x) in the case of fentanyl (0.028 mg/kg) but markedly (36 x) in the case of morphine (0.22 mg/kg). To reverse completely the antidiarrheal effect of equivalent analgesic doses of the opioids (their ED50S for analgesia lasting 2 hours), much more naloxone was required in the case of morphine (5.4 mg/kg) than in the case of fentanyl (0.19 mg/kg). After oral administration, the difference between both opioids was less pronounced. Analgesia was obtained at 0.85 mg/kg with fentanyl and 32 mg/kg with morphine. This analgesic dose only slightly (1.7 x) exceeded the antidiarrheal dose in the case of fentanyl (0.49 mg/kg) but significantly (6.2 x) in the case of morphine (5.2 mg/ kg). To reverse completely the antidiarrheal effect of equivalent analgesic oral doses of the opioids (their ED50S for analgesia lasting 2 hours), more naloxone was required in the case of morphine (11 mg/kg) than in the case of fentanyl (2.0 mg/kg). Rapid penetration of fentanyl into the brain is thought to be responsible for small dissociation between the analgesic and intestinal effect of this lipophilic opioid. The present data provide preclinical evidence to support the relatively low incidence of intestinal side effects observed clinically with the use of TTS-fentanyl in comparison with orally administered morphine.     

Concurrent mapping of brain sites for sensitivity to the direct application of morphine and focal electrical stimulation in the production of antinociception in the rat

The effect of morphine microinjection (5 microgram/0.5 microliter) and focal electrical stimulation on the animal's response to radiant heat and noxious pinch was studied concurrently at 117 brain loci extending from the medial thalamus caudally to the periaqueductal gray area (PAG). Three populations of brain sites were discernible based on their responsiveness to focal electrical stimulation and morphine microinjection in the production of antinociception: (a) sites which support stimulation-produced analgesia (SPA, n = 24), (b) sites which were sensitive to the direct application of morphine (n = 8), (c) sites responsive to both manipulations (n = 8). With a few exceptions, all morphine sensitive sites were located within the anatomical boundaries of the PAG while sites supporting SPA were located not only within the PAG but also in the brain regions peripheral to this structure. Sites responsive to both manipulations were generally distributed throughout thf lateral aspect of the posteroventral PAG. Stimulation strength-effect curves for sites subserving SPA were also obtained. No differences were discovered between curves obtained from morphine-sensitive and -insensitive brain loci.     

Evidence for a role of N-methyl-D-aspartate receptors in L-arginine-induced attenuation of morphine antinociception

Twice daily injections of L-arginine (50, 100 or 200 mg/kg, i.p.) for 4 days dose-dependently, decreased morphine antinociception in male Swiss-Webster mice as measured by the tail-flick test. To determine the possible role of N-methyl-D-aspartate (NMDA) receptor in the action of L-arginine, the effects of MK-801, a noncompetitive antagonist of the NMDA receptor and of LY 235959, a competitive antagonist of the NMDA receptor on L-arginine-induced attenuation of morphine antinociception were determined. MK-801 (0.01-0.10 mg/kg, i.p.) or LY 235959 (1.0-4.0 mg/kg, i.p.) given 10 min before each injection of L-arginine (200 mg/kg, i.p.) reversed the action of the letter in a dose-dependent manner on morphine antinociception. It is concluded that NMDA receptors are involved in the action of L-arginine in attenuating morphine antinociception.     

Spinal cholinergic and monoamine receptors mediate the antinociceptive effect of morphine microinjected in the periaqueductal gray on the rat tail, but not the feet

The antinociceptive effects of morphine (5 micrograms) microinjected into the ventrolateral periaqueductal gray were determined using both the tail flick and the foot withdrawal responses to noxious radiant heating in lightly anesthetized rats. Intrathecal injection of appropriate antagonists was used to determine whether the antinociceptive effects of morphine were mediated by alpha 2-noradrenergic, serotonergic, opioid, or cholinergic muscarinic receptors. The increase in the foot withdrawal response latency produced by microinjection of morphine in the ventrolateral periaqueductal gray was reversed by intrathecal injection of the cholinergic muscarinic receptor antagonist atropine, but was not affected by the alpha 2-adrenoceptor antagonist yohimbine, the serotonergic receptor antagonist methysergide, or the opioid receptor antagonist naloxone. In contrast, the increase in the tail flick response latency produced by morphine was reduced by either yohimbine, methysergide or atropine. These results indicate that microinjection of morphine in the ventrolateral periaqueductal gray inhibits nociceptive responses to noxious heating of the tail by activating descending neuronal systems that are different from those that inhibits the nociceptive responses to noxious heating of the feet. More specifically, serotonergic, muscarinic cholinergic and alpha 2-noradrenergic receptors appear to mediate the antinociception produced by morphine using the tail flick test. In contrast, muscarinic cholinergic, but not monoamine receptors appear to mediate the antinociceptive effects of morphine using the foot withdrawal response.     

Antinociception mediated by the periaqueductal gray is attenuated by orphanin FQ

Orphanin FQ or nociceptin (OFQ/N(1-17)) is a recently discovered peptide which, upon intracerebroventricular administration, reverses opioid-mediated analgesias. OFQ/N(1-17) terminals are located in the periaqueductal gray (PAG), a structure known to be involved in pain modulation, suggesting that the functional anti-opioid effects of OFQ/N(1-17) are mediated by PAG neurons. To test this, subsequent microinjections of morphine or kainic acid and OFQ/N(1-17) were made into the PAG of awake rats. Administration of OFQ/N(1-17) attenuated the tail flick inhibition produced by both morphine and kainic acid microinjection. OFQ/N(1-17) attenuation of antinociception produced by a neuroexcitant indicates that OFQ/N(1-17) reverses opioid antinociception by inhibiting PAG output neurons.     

Endogenous opioid peptides acting at mu-opioid receptors in the dorsal horn contribute to midbrain modulation of spinal nociceptive neurons

Activation of neurons in the midbrain periaqueductal gray (PAG) inhibits spinal dorsal horn neurons and produces behavioral antinociception in animals and analgesia in humans. Although dorsal horn regions modulated by PAG activation contain all three opioid receptor classes (mu, delta, and kappa), as well as enkephalinergic interneurons and terminal fields, descending opioid-mediated inhibition of dorsal horn neurons has not been demonstrated. We examined the contribution of dorsal horn mu-opioid receptors to the PAG-elicited descending modulation of nociceptive transmission. Single-unit extracellular recordings were made from rat sacral dorsal horn neurons activated by noxious heating of the tail. Microinjections of bicuculline (BIC) in the ventrolateral PAG led to a 60-80% decrease in the neuronal responses to heat. At the same time, the responses of the same neurons to iontophoretically applied NMDA or kainic acid were not consistently inhibited. The inhibition of heat-evoked responses by PAG BIC was reversed by iontophoretic application of the selective mu-opioid receptor antagonists, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP). A similar effect was produced by naloxone; however, naloxone had an excitatory influence on dorsal horn neurons in the absence of PAG-evoked descending inhibition. This is the first demonstration that endogenous opioids acting via spinal mu-opioid receptors contribute to brain stem control of nociceptive spinal dorsal horn neurons. The inhibition appears to result in part from presynaptic inhibition of afferents to dorsal horn neurons.     

Opioid regulation of gonadotropin-releasing hormone gene expression in the male rat brain as studied by in situ hybridization

It is well documented that gonadotropin-releasing hormone (GnRH) release is negatively regulated by opiates. In order to investigate the role of opiates in the regulation of GnRH gene expression in the rat brain, we studied the effects of chronic administration of the opioid drug morphine and an opiate receptor antagonist naloxone on GnRH mRNA levels as measured by in situ hybridization. Four-day treatment with morphine (40 mg kg day-2) produced a 44% decrease in the number of silver grains overlying GnRH neurones. Conversely, naloxone (4 mg kg day-2) also administered during 4 days increased by hybridization signal by 22%. The concomitant administration of morphine and naloxone completely prevented the effect of morphine on GnRH gene expression indicating the inhibitory influence of morphine is likely to be mediated by opioid receptors. The present data clearly indicate that opiates can inhibit not only the release of GnRH and consequently LH secretion but also the biosynthesis of the neuropeptide as evaluated by mRNA level measurements.     

Possible mechanisms of salt-induced hypertension in Dahl salt-sensitive rats

The effects of acute and chronic administration of cocaine on the antinociception and tolerance to the antinociceptive actions of mu-(morphine), kappa-(U-50,488H), and delta-([D-Pen2,D-Pen5]enkephalin; DPDPE), opioid receptor agonists were determined in male Swiss-Webster mice. Intraperitoneal injection of 40 mg/kg of cocaine by itself produced weak antinociceptive response as measured by the tail-fick test but the lower doses were ineffective. Administration of morphine (10 mg/kg, SC), U-50,488H (25 mg/kg, IP) or DPDPE (10 microg/mouse, ICV) produced antinociception in mice. Cocaine (20 mg/kg) potentiated the antinociceptive action of morphine and DPDPE but had no effect on U-50,488H-induced antinociception. Administration of morphine (20 mg/kg, SC), U-50,488H (25 mg/kg, IP) or DPDPE (20 microg/mouse, ICV) twice a day for 4 days resulted in the development of tolerance to their antinociceptive actions. Tolerance to the antinociceptive actions of morphine and U-50,488H was inhibited by concurrent treatment with 20 or 40 mg/kg doses of cocaine; however, tolerance to the antinociceptive action of DPDPE was not modified by cocaine. It is concluded that cocaine selectively potentiates the antinociceptive action of mu- and delta- but not of the kappa-opioid receptor agonist. On the other hand, cocaine inhibits the development of tolerance to the antinociceptive actions of mu- and kappa- but not of delta-opioid receptor agonists in mice.     

A lateralized deficit in morphine antinociception after unilateral inactivation of the central amygdala

The amygdala is a forebrain region that is receiving increasing attention as a modulator of pain sensation. The amygdala contributes to antinociception elicited by both psychological factors (e.g., fear) and exogenous opioid agonists. Unlike the midbrain periaqueductal gray matter (PAG) or rostral ventromedial medulla, the amygdala is a pain-modulating region that has clear bilateral representation in the brain, making it possible to determine whether pain-modulating effects of this region are lateralized with respect to the peripheral origin of noxious stimulation. Unilateral inactivation of the central nucleus of the amygdala (Ce) plus adjacent portions of the basolateral amygdaloid complex (with either the excitotoxin NMDA or the GABAA agonist muscimol) reduced the ability of morphine to suppress prolonged, formalin-induced pain derived from the hindpaw ipsilateral, but not contralateral, to the inactivated region. This effect was evident regardless of the nociceptive scoring method used (weighted scores or flinch-frequency method) and was not accompanied by a concurrent reduction in morphine-induced hyperlocomotion. Unilateral lesions restricted to the basolateral amygdaloid complex (i.e., not including the Ce) did not reduce the ability of morphine to suppress formalin-induced pain derived from either hindpaw. The results constitute the first report of a lateralized deficit in opioid antinociception after unilateral inactivation of a specific brain area and show the first clear neuroanatomical dissociation between antinociceptive and motor effects of systemically administered morphine in the rat. The amygdala appears to modulate nociceptive signals entering the ipsilateral spinal dorsal horn, probably through monosynaptic connections with ipsilateral portions of the PAG.     

ACEA-1328, an NMDA receptor antagonist, increases the potency of morphine and U50,488H in the tail flick test in mice

The effect of 5-nitro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1328), a competitive and systemically bioavailable NMDA receptor/glycine site antagonist, was examined on opioid-induced antinociception in the tail flick test. Swiss Webster mice were injected with ACEA-1328 either alone or in combination with morphine or (+/-)-trans-U-50488 methanesulfonate (U50,488H), a mu- and a kappa-opioid receptor agonist, respectively, and tested for antinociception. Systemic administration of ACEA-1328 alone increased the tail flick latencies with an ED50 of approximately 45 mg kg-1. Concurrent administration of ACEA-1328 with morphine, or U50,488H, at doses that did not affect tail flick latencies, potentiated the antinociceptive effect of the opioid analgesics and vice versa. Naloxone, an opioid receptor antagonist, while not modifying the effect of ACEA-1328, did block the augmentation, suggesting that opioid receptors might be involved in the latter effect. 5-Aza-7-chloro-4-hydroxy-3-(m-phenoxyphenyl)quinoline-2(1H)-one (ACEA-0762), a selective NMDA receptor/glycine site antagonist, also showed enhancement of the antinociceptive effect of morphine and U50,488H. However, concurrent administration of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzol[f]quinoxaline (NBQX), a selective non-NMDA receptor antagonist, with morphine did not alter the antinociceptive potency of the opioid analgesic. Overall, the data suggest that ACEA-1328 may increase the potency of the opioid analgesics by antagonising the glycine site associated with the NMDA receptor.     

The Pain Beliefs and Perceptions Inventory: further evidence for a 4-factor structure

Clinical observations have suggested that cholestasis is associated with increased neurotransmission mediated by the opioid system in the central nervous system. As opiate agonists (e.g. morphine) mediate analgesia, increased opioidergic tone in cholestasis should be associated with a decreased response to pain. To test this hypothesis, the response of rats with acute cholestasis to a nociceptive stimulus was measured by the use of the tail-flick test, an extensively validated assay for measuring opiate-induced antinociception. Five and 7 days after bile-duct resection, the mean tail-flick latency was longer than before surgery (p < 0.05), whereas the corresponding means for unoperated and sham-resected controls were not significantly different from their respective baseline values. The increase in the mean tail-flick latency in the bile-duct resection group was reversed by (-)-naloxone (1 mg/kg subcutaneously), but not by its enantiomer (+)-naloxone (10 mg/kg subcutaneously) (p < 0.001). The stereoselective reversal of antinociception in cholestasis by naloxone indicates that this phenomenon is opioid-receptor mediated. In contrast, prolongation of the mean TFL found in the rat model of thioacetamide-induced acute hepatocellular necrosis was not reversed by (-)-naloxone, indicating that antinociception in this model is not opioid mediated. These findings provide support for the hypothesis that cholestasis is associated with increased opioidergic tone.     

Tolerance to the antinociceptive effect of morphine microinjections into the ventral but not lateral–dorsal periaqueductal gray of the rat.

Tolerance to the antinociceptive effect of morphine is mediated at least in part by morphine's action within the periaqueductal gray (PAG). The objective of the present study was to determine whether both ventral and lateral-dorsal PAG regions contribute to the development of tolerance. It was found that the antinociceptive efficacy of microinjecting morphine (5 μg/0.4 μl) into the ventral but not the lateral-dorsal PAG diminished with successive injections. Control experiments indicated that this decrease was caused by tolerance to morphine and was not a result of cell death caused by repeated microinjections or habituation from repeated behavioral testing. The finding of greater susceptibility of the ventral compared with the lateral-dorsal PAG to the development of tolerance adds to a growing literature distinguishing antinociception from these two regions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Osmotic concentration of polypeptides from hemofiltrate of uremic patients

In order to clarify the interactions between various doses of thiopental and fentanyl in producing "balanced anaesthesia", their effects on consciousness, superficial nociception, and respiration and circulation were studied during N2O+O2 inhalation in connection with the induction of anaesthesia. Altogether 60 patients were studied; the drug combinations used were thiopental 5 mg/kg (TP5), thipental 3 mg/kg (TP3), thiopental 3 mg/kg and fentanyl 0.5 micrograms/kg (TP3F0.5), thiopental 2 mg/kg and fentanyl 1 micrograms/kg (TP2F1), thiopental 1 mg/kg and fentanyl 2 micrograms/kg (TP1F2), and fentanyl 3 micrograms/kg (F3). Five minutes after the i.v. supplementation of N2O+O2 anaesthesia, the depth of anaesthesia and analgesia (antinociception) were evaluated from the eyelid reflex and by pinching an inguinal skin fold. Cardiorespiratory parameters were measured during this study period at 1-min intervals. The balance between antinociception and anaesthesia was closest to optimum in groups TP2F1 and TP2F0.5. In pure thiopental groups, the analgesia was poor; only four patients did not respond to the nociceptive stimulus, whereas in group F3 anaesthesia (disappearance of the eyelid reflex) was obtained in only two patients. The respiratory depression was most pronounced in groups receiving 3, 2 and 1 micrograms/kg fentanyl and weakest in groups where only thiopental was used. Blood pressure decreased in all groups but no statistically significant differences were noted. On the basis of the results it seems obvious that attempts to achieve what is called "balanced anaesthesia" by the supplementation of an N2O+O2 mixture with fentanyl only leads to an unnecessarily prnounced respiratory depression, whereas supplementation with thiopental alone does not offer adequate antinociception.     

The central nucleus of the amygdala contributes to the production of morphine antinociception in the formalin test

The rat paw formalin test is a model of prolonged pain due to mild tissue injury. There is some evidence suggesting that morphine does not produce antinociception in the formalin test via the brain-stem and spinal cord circuitry normally associated with antinociception. Furthermore, morphine appears to require an intact forebrain in order to function as an analgesic for formalin pain. In the 2 experiments reported here, we investigated the possibility that the central nucleus of the amygdala (Ce) contributes to the production of morphine antinociception (MA) in the formalin test. Nociception in this test occurs in 2 phases, with the 1st phase occurring 0-5 min after formalin injection and the 2nd phase beginning 10-15 min after injection and continuing for approximately 1 h. In Exp. 1, bilateral neurotoxic lesions of the Ce, but not lesions of the adjacent basolateral nucleus (BL), reliably attenuated MA (7 mg/kg morphine sulfate) during the 2nd phase of the formalin test without affecting baseline nociception. These results were obtained regardless of whether the rating scale method or flinch-frequency method of nociceptive scoring was used. During the 1st phase, Ce lesions reliably attenuated MA as measured by the flinch-frequency method, but not as measured by the rating scale method. In Exp. 2, Ce lesions also reliably attenuated the antinociception produced by 12 mg/kg morphine sulfate during the 2nd phase of the formalin test. Antinociception appeared to be almost completely re-instated, however, if the dose of morphine was raised to 20 mg/kg. The results indicate that neurons originating from the Ce contribute to the production of MA during the 2nd phase, and possibly the 1st phase, of the formalin test, especially at relatively lower doses of morphine. This suggests that in addition to coordinating conditioned antinociceptive responses, the amygdala may be a component of endogenous antinociceptive circuitry. These and other issues are discussed with reference to the spino-ponto-amygdaloid nociceptive pathway, and the proposed role of the amygdala in the mediation of defense reactions.     

Age-related decrease in centrally-mediated pressor response to clonidine in conscious rats

Nitric oxide (NO) is a neuronal messenger that it is thought to be involved in the nociceptive transmission modulation. The activity of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) was shown to be identical to NOS activity in the brain. Since the periaqueductal gray matter (PAG) plays an important role in pain perception and antinociception this study was carried out to monitor the expression of NADPH-d in PAG after nociceptive visceral stimulation. Our data showed that the noxious visceral stimulation significantly increased NADPH-d positive neurons and that these neurons were localized in the ventrolateral areas of the PAG. These findings suggest that NO in the PAG may play a role in pain modulation and antinociception.