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Biomedical subjects

S N Raja

Publications and source records attributed to S N Raja.

At least 19 recordsLinked to original sources
PubMed2004

Differential roles of neuronal and endothelial nitric oxide synthases during carrageenan-induced inflammatory hyperalgesia.

The present study investigated the role of neuronal nitric oxide synthase (nNOS) in carrageenan-induced inflammatory pain by combining genomic and pharmacological strategies. Intrathecal injection of the nNOS inhibitor 7-nitroindazole dose-dependently inhibited carrageenan-induced thermal hyperalgesia in both early and late phases in wild-type mice. However in nNOS knockout mice, carrageenan-induced thermal hyperalgesia remained intact in the early phase but was reduced in the late phase. Spinal Ca2+ -dependent nitric oxide synthase (NOS) activity in nNOS knockout mice was significantly lower than that in wild-type mice. Following carrageenan injection, although the spinal Ca2+ -dependent NOS activity in both wild-type and knockout mice increased, the enzyme activity in nNOS knockout mice reached a level similar to that in wild-type mice. On the other hand, no significant difference in spinal Ca2+ -independent NOS activity was noted between wild-type and nNOS knockout mice before and after carrageenan injection. Furthermore, intrathecal administration of the endothelial NOS (eNOS) inhibitor L-N5-(1-iminoethyl)-ornithinein nNOS knockout mice inhibited the thermal hyperalgesia in both early and late phases, though this inhibitor had no effect in wild-type mice. Meanwhile, Western blot showed that eNOS expression in the spinal cord of nNOS knockout mice was up-regulated compared with wild-type mice; immunohistochemical staining showed that the spinal eNOS was mainly distributed in superficial laminae of the dorsal horn. Finally, double staining with confocal analysis showed that the enhanced spinal eNOS was expressed in astrocytes, but not in neurons. Our current results indicate that nNOS plays different roles in the two phases of carrageenan-induced inflammatory pain. In this model, enhanced spinal eNOS appears to compensate for the role of nNOS in nNOS knockout mice.

Animals↗
PubMed2003

Intact carrageenan-induced thermal hyperalgesia in mice lacking inducible nitric oxide synthase.

To date, the exact role of inducible nitric oxide synthase (iNOS) in inflammatory pain remains controversial. In the present study, we combined a pharmacological strategy (using a selective iNOS inhibitor) with a genomic strategy (using mice lacking the iNOS gene) to address the function of iNOS in the central mechanism of carrageenan-induced persistent inflammatory pain. In the wild type mice, intrathecal administration of L-N(6)-(1-iminoethyl)-lysine, a selective iNOS inhibitor, significantly inhibited thermal hyperalgesia in the late phase but not in the early phase of carrageenan inflammation. Moreover, iNOS mRNA expression in the lumbar enlargement segments of the spinal cord was dramatically induced at 24 h (late phase) after injection of carrageenan into a hind paw. Interestingly, targeted disruption of iNOS gene did not affect carrageenan-induced thermal hyperalgesia in either the early (2-6 h) or late phase. In the lumbar enlargement segments of iNOS knockout mice, nitric oxide synthase (NOS) enzyme activity remained at a similar level to that of the wild type mice at 24 h after carrageenan injection. We found that intrathecal administration of 7-nitroindazole (a selective neuronal NOS inhibitor), but not L-N(5)-(1-iminoethyl)-ornithine (a selective endothelial NOS inhibitor), significantly reduced carrageenan-induced thermal hyperalgesia in both the early phase and the late phase in iNOS knockout mice. We also found that expression of neuronal NOS but not endothelial NOS in the lumbar enlargement segments was significantly increased in iNOS knockout mice compared with wild type mice at 24 h after carrageenan injection. Our results indicate that neuronal NOS might compensate for the function of iNOS in the late phase of carrageenan-induced inflammatory pain in iNOS knockout mice. This suggests that iNOS may be sufficient, but not essential, for the late phase of the carrageenan-induced thermal hyperalgesia.

Animals↗
PubMed2002

Opioids versus antidepressants in postherpetic neuralgia: a randomized, placebo-controlled trial.

BACKGROUND: Tricyclic antidepressants (TCA) provide less than satisfactory pain relief for postherpetic neuralgia (PHN), and the role of opioids is controversial. OBJECTIVE: To compare the analgesic and cognitive effects of opioids with those of TCA and placebo in the treatment of PHN. METHODS: Seventy-six patients with PHN were randomized in a double-blind, placebo-controlled, crossover trial. Each subject was scheduled to undergo three treatment periods (opioid, TCA, and placebo), approximately 8 weeks' duration each. Doses were titrated to maximal relief or intolerable side effects. The primary outcome measures were pain intensity (0 to 10 scale), pain relief (0 to 100%), and cognitive function. Analyses included patients who provided any pain ratings after having received at least a single dose of a study medication. RESULTS: Fifty patients completed two periods, and 44 patients completed all three. Mean daily maintenance doses were morphine 91 mg or methadone 15 mg and nortriptyline 89 mg or desipramine 63 mg. Opioids and TCA reduced pain (1.9 and 1.4) more than placebo (0.2; p < 0.001), with no appreciable effect on any cognitive measure. The trend favoring opioids over TCA fell short of significance (p = 0.06), and reduction in pain with opioids did not correlate with that following TCA. Treatment with opioids and TCA resulted in greater pain relief (38 and 32%) compared with placebo (11%; p < 0.001). More patients completing all three treatments preferred opioids (54%) than TCA (30%; p = 0.02). CONCLUSIONS: Opioids effectively treat PHN without impairing cognition. Opioids and TCA act via independent mechanisms and with varied individual effect.

Adult↗
PubMed2002

The role of mu-opioid receptors in inflammatory hyperalgesia and alpha 2-adrenoceptor-mediated antihyperalgesia.

The purpose of the present study was to investigate the role of mu-opioid receptor in inflammatory hyperalgesia in intact and in spinalized animals and the interaction between mu-opioid and alpha2-adrenergic receptor in acute pain and inflammatory hyperalgesia. Behavioral responses to mechanical and heat stimuli were studied in mu-opioid receptor knockout mice and wildtype control mice. Thermal nociception was evaluated by measuring paw withdrawal latencies to radiant heat applied to the hindpaws. Mechanical nociception was measured by von Frey monofilament applications to the hindpaws. Intraplantar carrageenan-induced (1 mg/40 microl) mechanical and heat hyperalgesia were compared in micro-opioid knockout and wildtype mice. The effect of systemically administered alpha2-adrenergic receptor agonist dexmedetomidine (1-10 microg/kg) was evaluated on mechanical and thermal withdrawal responses under normal and inflammatory state in knockout and wildtype mice. The role of micro-opioid receptor in descending modulation of nociception was studied by assessing mechanical and heat withdrawal responses before and after mid-thoracic spinalization. Withdrawal responses to radiant heat and von Frey monofilaments were similar in mu-opioid knockout and wildtype mice before and after the carrageenan induced hindpaw inflammation. Also, antinociceptive effects of dexmedetomidine in thermal and mechanical nociceptive tests were similar before carrageenan induced hindpaw inflammation. However, the potency of dexmedetomidine was significantly reduced in carrageenan-induced mechanical hyperalgesia in mu-opioid knockout mice compared to the wildtype control mice. Thermal and mechanical withdrawal responses were similar between mu-opioid knockout and wildtype mice before and after mid-thoracic spinalization. Our observations indicate that the mu-opioid receptors do not play an important role in alpha2-adrenergic receptor agonist-mediated acute antinociception. In addition, micro-opioid receptors are not tonically involved in the modulation of inflammation-induced mechanical and thermal hyperalgesia, and the supraspinal control of spinal reflexes. However, in the presence of inflammation, mu-opioid receptors play an important role in the antihyperalgesic actions of an alpha2-adrenergic receptor agonist.

Adrenergic alpha-Agonists↗
PubMed2001

Heat, but not mechanical hyperalgesia, following adrenergic injections in normal human skin.

The development of adrenergic sensitivity in nociceptors has been suggested as a mechanism of neuropathic pain. We sought to determine if nociceptors in the skin of normal subjects exhibit adrenergic sensitivity. We investigated the effects of intradermal administration of norepinephrine, phenylephrine, and brimonidine on heat pain sensitivity. Norepinephrine and phenylephrine (in concentrations ranging from 0.1 to 10 microM by factors of 10), brimonidine (at 0.01-1 microM), and saline were injected (30 microl volume) in a random, double-blind manner to different sites on the volar surface of the forearm in ten subjects. Before and after the injections, heat testing was performed with a non-contact laser thermal stimulator. Heat pain threshold was measured by means of a 'Marstock' technique in which subjects pressed a reaction time key when they perceived that a slowly increasing heat stimulus (1 degrees C/s ramp from a 36 degrees C base) was painful. In addition, the subjects used magnitude estimation techniques to rate the intensity of pain to a suprathreshold heat stimulus (47 degrees C, 2 s). Mechanical testing was done using 200-microm diameter probes attached to calibrated weights that provided forces over the range of 16-512 mN. The intradermal injections of norepinephrine, phenylephrine and brimonidine produced little evoked pain. However, a dose-dependant decrease in heat pain threshold, but not mechanical pain threshold, was observed. At the highest drug dose injected, all three adrenergic compounds produced a significant decrease in heat pain threshold compared to the saline injection. A significant increase in response to the suprathreshold heat stimulus was also found. One possible explanation for this apparent heat hyperalgesia is that the decrease in perfusion due to the localized vasoconstriction may alter the heat response. However, in control studies we found that the non-adrenergic vasoconstrictors, angiotensin II and vasopressin did not produce heat hyperalgesia at doses that produced comparable decreases in blood flow. In addition, occlusion of blood flow with a blood pressure cuff did not lead to heat hyperalgesia. Thus, the heat hyperalgesia observed with the adrenergic agonists is not due to a decrease in perfusion associated with the injection. These results indicate that alpha(1)- and alpha(2)-adrenoceptor-mediated mechanisms may play a role in sensitization of nociceptors to heat stimuli in normal skin.

Adolescent↗
PubMed2001

Soy-containing diet suppresses chronic neuropathic sensory disorders in rats.

UNLABELLED: Partial sciatic nerve ligation (PSL) in rodents produces chronic neuropathic sensory disorders resembling neuropathic pain in humans. We previously reported that levels of allodynia and hyperalgesia after PSL injury were markedly attenuated by consumption of soy-containing diets. Here we aimed to show that dietary effect on pain behavior is not specific to a certain laboratory. For this purpose, experiments were conducted in a different laboratory (Baltimore rather than Jerusalem) and a different rat strain (Wistar rather than Sabra), with additional and different testing methods (radiant heat from a lamp rather than a CO(2) laser). Rats were fed two soy-free diets and a soy-containing one for 28 days. The sensitivity of rats to nonnoxious and noxious stimuli was determined before PSL injury, and levels of neuropathic sensory disorders were determined after it. We found that consuming the soy-containing diet prevented development of tactile and heat allodynia, but not mechanical hyperalgesia. This dietary effect was not correlated with calorie intake and weight gain or dietary concentration of fat and carbohydrates. We conclude that, regardless of experimental site, diet markedly affects chronic neuropathic sensory disorders in rats and should be standardized in animal models of pain. IMPLICATIONS: Levels of chronic sensory disorders in a rat model of allodynia and hyperalgesia after partial sciatic nerve ligation depend on the consumption of a soy-containing diet. Further studies are needed to determine the role of diet in humans with chronic pain.

Animals↗
PubMed2001

Sensory processing in the deep spinal dorsal horn of neurokinin-1 receptor knockout mice.

BACKGROUND: The neurokinin-1 receptor and its primary ligand, substance P, are widely recognized as contributing to the spinal processing of nociceptive stimuli, yet the specific function of the neurokinin-1 receptor remains unclear. METHODS: To better clarify these functions, the authors examined the neurophysiologic responses of L4-L5 neurons in the deep dorsal horn to acute mechanical, thermal, and electrical stimuli in knockout and wild-type mice. In addition, the capacity of knockout and wild-type mice to show wind-up to repeated C-fiber stimuli and to show sensitization after cutaneous mustard oil was assessed. RESULTS: A total of 68 nociceptive neurons (35 in knockout, 33 in wild type) in laminae III-V were studied. No differences in the acute responses of neurons in knockout and wild-type mice to graded mechanical, thermal, or electrical stimuli or in the acute responses to mustard oil were observed. However, wind-up to repeated electrical stimulation at C-fiber intensity was significantly attenuated in the knockout mice compared with wild type controls. In addition, mustard oil-induced mechanical hypersensitivity was significantly reduced in the knockout mice. CONCLUSIONS: These results indicate that neurokinin-1 receptors do not play a significant role in the responses of nociceptive neurons in the deep spinal dorsal horn to acute noxious mechanical, thermal, electrical, or chemical stimuli. On the other hand, neurokinin-1 receptors are critical for the central hyperexcitability that is observed in these neurons with repeated C-fiber inputs and to the central sensitization induced by topical mustard oil application.

Animals↗
PubMed2001

Consumption of soy diet before nerve injury preempts the development of neuropathic pain in rats.

BACKGROUND: A previous report using a partial sciatic nerve ligation (PSL) model for neuropathic pain in rats demonstrated that consumption of soy-containing diets preoperatively and postoperatively suppressed development of mechanical and heat allodynia, as well as hyperalgesia. The current study examined whether dietary soy suppresses these neuropathic sensory disorders when consumed either before or after PSL injury. METHODS: Male Wistar rats were grouped into seven different feeding regimens. These rats were fed SOY (RMH-1000, PMI Feeds, St. Louis, MO), a diet containing 85% soy protein since weaning, and were then switched to noSOY (Bio-Serv Co., Frenchtown, NJ), a diet devoid of soy at certain time points before PSL injury (14, 7, 1 days, or 15 and 0 h). Postoperatively, these rats were fed SOY or noSOY diets. Levels of mechanical and heat allodynia and hyperalgesia were determined preoperatively and 3, 8, and 14 days after PSL injury. RESULTS: Compared with groups fed preoperative noSOY, consumption of SOY before PSL injury significantly blunted postoperative levels of allodynia and hyperalgesia. Administering the SOY diet both before and after PSL injury provided no additional suppression of neuropathic pain. No pain suppression was noted in rats fed a noSOY diet preoperatively and SOY diet after PSL injury. Switching from SOY to noSOY feeding within 15 h of PSL injury was sufficient to allow for the full development of allodynia and hyperalgesia. CONCLUSIONS: Consumption of a soy-containing diet suppressed the development of neuropathic pain after PSL injury. The pain-suppressing properties of dietary soy were the result of a preemptive effect (i.e., when consumed preoperatively), but not a palliative effect (i.e., when consumed postoperatively). This effect of soy-containing diets appears to be short-lived, since switching to a noSOY diet 15 h before ligation abrogated the suppressive effect of soy.

Animals↗
PubMed2000

Nerve injury-induced mechanical but not thermal hyperalgesia is attenuated in neurokinin-1 receptor knockout mice.

Mice lacking the gene encoding for substance P and neurokinin A, or the NK-1 receptor, exhibit alterations in behavior to various acute nociceptive stimuli. However, behavioral responses of NK-1 mutant animals have not been well characterized in models of chronic pain. We studied the behavioral responses of NK-1 knockout and wild-type control mice to thermal and mechanical stimuli before and after inducing chronic neuropathic pain by unilateral ligation of the L5 spinal nerve. Mechanical hyperalgesia was evaluated by determining the frequency of withdrawal to von Frey monofilaments applied to the hind paws. Nerve injury-induced hyperalgesia to thermal stimuli was examined by determining responses to radiant heat and cooling stimuli. The contribution of the sympathetic nervous system to mechanical hyperalgesia was evaluated by administering 3 mg/kg phentolamine, an alpha-adrenergic antagonist, subcutaneously. Following spinal nerve injury, withdrawal frequencies to mechanical stimulation increased in wild-type mice within 1 day and persisted during the 9-week observation period, whereas in the knockout mice, withdrawal frequencies did not increase significantly. In contrast, withdrawal latencies to radiant heat decreased up to 2 weeks after nerve injury in both the NK-1 and the wild-type mice. Similarly, the increase in withdrawal frequency to the cooling stimuli following the nerve injury was not different in the NK-1 knockout and wild-type mice. Mechanical hyperalgesia in the wild-type mice was not reversed by systemic administration of phentolamine, suggesting that the pain is not sympathetically maintained. The results indicate that NK-1 receptors contribute to the development of mechanical, but not thermal, hyperalgesia in neuropathic pain.

Animals↗
PubMed2000

Psychiatric symptoms and distress differ between patients with postherpetic neuralgia and peripheral vestibular disease.

OBJECTIVE: No previous studies have investigated the psychiatric characteristics of patients with postherpetic neuralgia (PHN). Similarly, no studies have been performed on patients with different chronic somatic symptoms due to a defined medical disease to compare the characteristics of psychiatric morbidity associated with each etiology. METHODS: After completing the subscales of the Symptom Checklist 90-R, a psychiatrist administered the Diagnostic Interview Schedule to all subjects. The psychiatric comorbidity in 35 patients with pain due to PHN was compared with a control group of 34 patients with the nonpainful aversive symptom of vertigo due to a peripheral vestibular disorder that caused unilateral hypofunction. RESULTS: PHN patients had significantly more symptoms of major depression and somatization disorder. No significant differences were found between groups for psychiatric diagnoses. Patients with PHN reported significantly less acutely distressing somatic symptoms. CONCLUSION: These results suggest that the psychiatric symptoms of patients with PHN are distinct from nonspecific acute distress and may be related to the experience of suffering from chronic neuropathic pain. Patients with PHN may not meet criteria for a psychiatric diagnosis, but their psychiatric comorbidity places them at substantial risk for increased pain, suicidal ideation, sustained disability, and the numerous complications of excessive medical evaluation and treatment. Patients with PHN should be evaluated specifically for psychiatric symptoms to reduce potential negative consequences through appropriate treatment.

Adaptation, Psychological↗
PubMed2000

Comparison of lower extremity cutaneous temperature changes in patients receiving lumbar sympathetic ganglion blocks versus epidural anesthesia.

STUDY OBJECTIVE: To investigate if paravertebral lumbar sympathetic ganglion block and lumbar epidural anesthesia result in comparable cutaneous temperature changes in the lower extremity. DESIGN: Nonrandomized comparison study. SETTING: Operating rooms and pain clinic procedure rooms in a tertiary care hospital. PATIENTS AND INTERVENTIONS: 18 patients undergoing lumbar sympathetic ganglion blocks for the diagnosis and/or treatment of chronic pain, and 13 patients undergoing lumbar epidural anesthesia for radical prostatectomy. MEASUREMENTS: Cutaneous temperatures were measured over the great toe, calf, and thigh in all patients. Mean maximum temperature (Tmax), rate of change of skin temperature (from 5% to 95% of maximum temperature change), and mean time to 1 degrees C increase, and 50% and 95% of maximum temperature change for each group were compared. Temperature changes for the epidural and lumbar sympathetic block patients were compared. MAIN RESULTS: Epidural and lumbar sympathetic block resulted in similar Tmax (34.1 +/- 0.2 and 33.8 +/- 0.9 degrees C, respectively, mean +/- SEM; p = 0.18) and rate of temperature change (0.64 +/- 0.09 and 0.49 +/- 0.07 degrees C/min; p = 0.2) in the great toe. The onset of cutaneous temperature change after lumbar sympathetic block was slower than after epidural anesthesia (1 degrees C increase: 17 and 11 min, respectively, 50% of Tmax: 25 and 17 min, respectively, and 95% of Tmax: 40 and 31 min, respectively; p < 0.05 for each). CONCLUSIONS: The similar rate and magnitude of cutaneous temperature change in the distal lower extremity suggests the degree of sympathetic blockade is similar with lumbar sympathetic blockade and epidural anesthesia. Either technique should provide adequate sympathectomy for treating sympathetically maintained pain once the diagnosis has been confirmed using selective sympathetic blockade.

Adult↗
PubMed2000

Lumbar sympathetic block for sympathetically maintained pain: changes in cutaneous temperatures and pain perception.

UNLABELLED: Lumbar sympathetic block (LSB) is used in the management of sympathetically maintained pain states. We characterized cutaneous temperature changes over the lower extremities after LSB. Additionally, we examined the effects of iohexol, a radio-opaque contrast medium, on temperature changes and pain relief. After institutional review board approval and written, informed consent, 28 LSBs were studied in 17 patients. Iohexol or normal saline was injected in a randomized, double-blinded fashion before bupivacaine. Lower extremity cutaneous temperatures were measured. Pain, allodynia, interference with daily function, and perceived pain relief were reported in a subset of 15 LSBs for 1 wk after the block. The distal lower extremity ipsilateral to the LSB had the greatest magnitude (8.7 degrees +/- 0.8 degrees C) and rate (1.1 degrees +/- 0.2 degrees C/min) of temperature change. The great toe temperature was within 3 degrees C of core temperature within 35 min after LSB. There were no differences in temperature change between the groups. The iohexol group had greater relief of pain until the morning of the first postblock day (P = 0.002) and longer perceived relief of pain (P = 0.01). The maximum temperature of the great toe correlated with allodynia relief (P = 0.0007). Thus clinicians should expect ipsilateral toe temperatures to increase to within approximately 3 degrees C of core temperature. Iohexol does not alter the efficacy of LSB and may improve relief of symptoms. The magnitude of temperature change may predict relief of allodynia. IMPLICATIONS: Cutaneous toe temperatures approaching core temperature provide a useful monitor of lumbar sympathetic block and may predict relief of sympathetically maintained pain. Iohexol will not compromise temperature changes or pain relief.

Adult↗
PubMed2000

Heterogenous patterns of sensory dysfunction in postherpetic neuralgia suggest multiple pathophysiologic mechanisms.

BACKGROUND: Postherpetic neuralgia (PHN) is considered by some investigators to be predominantly a deafferentation-type central pain syndrome; others suggest that activity of remaining peripheral nociceptors plays a critical role. The authors investigated the sensory dysfunction in subjects with PHN of varying duration and at different sites to gain further insight into the mechanisms responsible for the clinical features of neuropathic pain. In addition, the relationships between ongoing pain and pain evoked by mechanical and thermal stimuli were compared in patients with trigeminal and truncal PHN, to determine if the pathophysiologic mechanisms differed among subjects. METHODS: In 63 subjects with PHN, quantitative sensory testing was performed in the region of maximum allodynia or ongoing pain and the corresponding contralateral site. The intensity of ongoing pain was recorded. Sensory thresholds for warmth, coolness, heat pain, and cold pain were determined. Pain induced by various mechanical stimuli (dynamic, static, punctate) was rated using a numerical rating scale of 0-10. RESULTS: The mean rating of ongoing PHN pain was 7.3 +/- 2.0 (mean +/- SD). Allodynia induced by one or more mechanical stimuli was observed in 78% of subjects. A smaller subset (40%) had hyperalgesia to heat or cold stimuli. In subjects with duration of PHN of < or = 1 yr duration, but not in those with duration of > 1 yr, the intensity of ongoing pain correlated with intensity of allodynia induced by dynamic stimuli. Deficits in thresholds for heat and cold pain were observed in the affected region of subjects with PHN in the thoracic dermatomes (P < 0.005), but not in the trigeminal distribution. No relationship was observed between the thermal deficits and ongoing pain or mechanical allodynia in the groups of subjects with either trigeminal or thoracic PHN. CONCLUSION: Despite a common cause, the patterns of sensory abnormalities differ between subjects. Particular differences were noted between groups with facial or truncal PHN and between groups with recent or more chronic PHN. The observations suggest that the relative contributions of peripheral and central mechanisms to the pathophysiology of pain differ among subjects and may vary over the course of PHN.

Adult↗
PubMed2000

Age-related thermoregulatory differences during core cooling in humans.

The current study assessed sympathetic neuronal and vasomotor responses, total body oxygen consumption, and sensory thermal perception to identify thermoregulatory differences in younger and older human subjects during core cooling. Cold fluid (40 ml/kg, 4 degrees C) was given intravenously over 30 min to decrease core temperature (Tc) in eight younger (age 18-23) and eight older (age 55-71) individuals. Compared with younger subjects, the older subjects had significantly lower Tc thresholds for vasoconstriction (35.5 +/- 0.3 vs. 36.2 +/- 0.2 degrees C, P = 0.03), heat production (35.2 +/- 0.4 vs. 35.9 +/- 0.1 degrees C, P = 0.04), and plasma norepinephrine (NE) responses (35.0 vs. 36.0 degrees C, P < 0.05). Despite a lower Tc nadir during cooling, the maximum intensities of the vasoconstriction (P = 0.03) and heat production (P = 0.006) responses were less in the older compared with the younger subjects, whereas subjective thermal comfort scores were similar. Plasma NE concentrations increased fourfold in the younger but only twofold in the older subjects at maximal Tc cooling. The vasomotor response for a given change in plasma NE concentration was decreased in the older group (P = 0.01). In summary, aging is associated with 1) a decreased Tc threshold and maximum response intensity for vasoconstriction, total body oxygen consumption, and NE release, 2) decreased vasomotor responsiveness to NE, and 3) decreased subjective sensory thermal perception.

Adolescent↗
PubMed1999

Characterization of mechanical withdrawal responses and effects of mu-, delta- and kappa-opioid agonists in normal and mu-opioid receptor knockout mice.

Clinical and experimental observations suggest that opiates can exert different influences on the perception of stimuli from distinct sensory modalities. Thermally-induced nociception is classically responsive to opiate agonists. mu-Opioid receptor-deficient transgenic mice are more sensitive to thermal nociceptive stimuli and morphine fails to attenuate the nociceptive responses to thermal stimuli in these animals. To enhance our understanding of opiate influences on mechanical sensitivity, we have examined withdrawal responses to a sequence of ascending forces of mechanical stimuli in mice with normal (wild type), half-normal (heterozygous) and absent (homozygous) mu-opioid receptor levels. We report data from mice examined without drug pretreatment or following pretreatment with morphine, the selective kappa-opioid agonist, U50488H, and the selective delta-opioid agonist, DPDPE. Saline-pretreated mice of each genotype displayed similar, monotonically increasing frequency of withdrawal responses to the graded stimuli. Subcutaneously administered morphine produced a dose-dependent reduction in withdrawal responses in wild type and heterozygous mice, but had no significant effect in homozygous mice. Intraventricular administration of DPDPE also reduced the frequency of paw withdrawal (FPW) in wild type mice, but not in homozygous mice. In contrast, systemic U50488H produced a dose-dependent attenuation of paw withdrawal in both wild type and homozygous mice. These findings suggest that (1) interactions of endogenous peptides with mu-opioid receptors may not play a significant role in the response to mechanical stimuli in drug-free animals, and (2) deficiency of mu-opioid receptors has no functional consequence on the response to the prototypical kappa-opioid receptor agonist, but decreases responses to the prototypical mu- and delta-opioid receptor agonists.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1999

Sympathectomy decreases formalin-induced nociceptive responses independent of changes in peripheral blood flow.

The present experiments studied the effect of surgical sympathectomy on mechanical paw withdrawal thresholds and formalin-induced pain behaviors (FIPB) and tested if the effect of sympathectomy on FIPB is dependent on changes in peripheral blood flow. Compared to sham-operated animals, surgical sympathectomy decreased second phase FIPB but did not affect paw withdrawal thresholds to mechanical stimuli. In sympathectomized and sham-operated animals, subcutaneous intraplantar injection of the nonadrenergic vasoconstrictor angiotensin II (20 microl, 1 mM) or the nonadrenergic vasodilator hydralazine (20 microl, 1 mM) prior to formalin injection decreased and increased peripheral blood flow, respectively. In sympathectomized animals, pretreatment with angiotensin II inhibited the increase of peripheral blood flow following formalin injection when compared to animals pretreated with saline or hydralazine. In sham-operated animals, pretreatment with hydralazine or angiotensin II did not alter vasodilation after formalin injection when compared to pretreatment with saline. Pretreatment with vasoactive drugs had no effect on the sympathectomy-induced decrease in FIPB. It is concluded that sympathectomy decreases FIPB by mechanisms that are independent of sympathectomy-induced changes in peripheral blood flow. The formalin test is an easy, reliable model that can be used to study the mechanisms by which the sympathetic nervous system modulates pain processing.

Animals↗
PubMed1999

Mechanical hyperalgesia after spinal nerve ligation in rat is not reversed by intraplantar or systemic administration of adrenergic antagonists.

The development of alpha-adrenergic sensitivity in cutaneous nociceptors has been postulated as a mechanism for sympathetically maintained pain (SMP). In order to characterize the adrenergic receptors involved, we investigated the effects of intraplantar administration of alpha1-(prazosin) and alpha2-(yohimbine) adrenergic antagonists and systemic injection of phentolamine, a non-specific alpha-adrenergic blocker, on allodynic/hyperalgesic behavior in an animal model thought to mimic SMP in humans. Peripheral neuropathy in rats was induced by tight ligation of the L5/L6 spinal nerves. Mechanical hyperalgesia was quantified with von Frey hairs applied either for 3 s or repetitively to the plantar surface of the hindpaw. Responses to the 3 s duration stimulus were used to determine the paw withdrawal threshold with the up-down paradigm and repetitive stimuli were used to determine the response incidence of paw withdrawal to a given von Frey hair. Mechanical thresholds on the ipsilateral paw decreased significantly after ligation and were stable over the following 3 weeks. Intradermal administration of yohimbine or prazosin did not significantly alleviate mechanical hyperalgesia in L5/L6 ligated animals. Also systemic administration of phentolamine (1 and 5 mg/kg) did not alleviate the increased incidence of paw withdrawal in L5/L6 spinal nerve ligated animals. These results suggest that an alpha adrenergic interaction between sympathetic efferent and somatic afferent fibers does not play a critical role for the maintenance of mechanical hyperalgesia in this model for neuropathic pain.

Adrenergic alpha-1 Receptor Antagonists↗