Biomedical subjects

James C Eisenach

Publications and source records attributed to James C Eisenach.

At least 19 recordsLinked to original sources

PubMed2006

Neuronal nitric oxide synthase is upregulated in a subset of primary sensory afferents after nerve injury which are necessary for analgesia from alpha2-adrenoceptor stimulation.

alpha2-Adrenoceptor (AR) agonists increase in analgesic potency and efficacy after peripheral nerve injury, and their effects are blocked by neuronal nitric oxide synthase (nNOS) inhibitors and M4 muscarinic receptor antagonists only after injury. We tested whether nNOS and M4 muscarinic receptors are co-expressed in the spinal cord, and whether destruction of a subset of sensory afferents which are essential to alpha2-AR analgesia would also destroy nNOS and M4 receptor expression. Male Sprague-Dawley rats underwent left L5 and L6 spinal nerve ligation. Lumbar spinal cord was removed and immunostained for M4 muscarinic receptors and nNOS alone and for co-expression. Others received intrathecal injection of saporin linked to an antibody to the neurotrophin receptor p75(NTR), which eliminates cells expressing this receptor and the analgesic effects of alpha2-AR agonists. nNOS staining of fibers in the superficial dorsal horn was dramatically increased after spinal nerve ligation, and this was abolished by saporin linked anti-p75(NTR) treatment. In contrast, nNOS staining in dorsal horn neurons was unaltered by these manipulations. M4 receptors were present on neurons in the dorsal horn, some of which co-expressed nNOS, but their pattern of expression was not altered by these manipulations. Peripheral nerve injury increases nNOS expression in fibers in the superficial dorsal horn, some of which likely express p75(NTR), and alpha2-AR agonists may reduce injury-induced sensitization by activation of nNOS in these fibers In contrast, changes in nNOS and M4 receptor location on spinal cord neurons are not responsible for increased analgesic potency of alpha2-AR agonists after nerve injury.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2006

Clonidine reduces hypersensitivity and alters the balance of pro- and anti-inflammatory leukocytes after local injection at the site of inflammatory neuritis.

Perineural alpha2-adrenoceptor activation relieves hypersensitivity induced by peripheral nerve injury or sciatic inflammatory neuritis. This effect is associated with a reduction in pro-inflammatory cytokines, as well as a reduction in local leukocyte number and their capacity to produce pro-inflammatory cytokines. Curiously, clonidine's antinociceptive effect appears with a 2-3-day delay after injection. Previous observations have shown that alpha-adrenoceptor activation induces apoptosis in leukocytes, which would reduce leukocyte number. Additionally, macrophage scavenging of apoptotic cells results in a shift to an anti-inflammatory phenotype, with expression of transforming growth factor (TGF)-beta1. We therefore examined the effects of perineural clonidine 24 h and 3 days after its injection on apoptosis, TGF-beta1 expression and lymphocyte and macrophage phenotype in acute sciatic inflammatory neuritis. Perineural clonidine reduced ipsilateral neuritis-induced hypersensitivity in a delayed manner (3 days after treatment), along with a reduction at this time in lymphocyte number and an increase in caspase-3 and TGF-beta1 expressing cells and macrophages co-expressing TGF-beta1 in the sciatic nerve. One day after injection clonidine treatment was associated with a reduction in lymphocytes and pro-inflammatory Th-1 cells as well as increased numbers of caspase-3 and TGF-beta1 expressing cells and macrophages co-expressing TGF-beta1 in sciatic nerve. Clonidine's effects were prevented by co-administration of an alpha2-adrenoceptor antagonist. These data suggest that alpha2-adrenoceptor activation in sciatic inflammatory neuritis increases local apoptosis and anti-inflammatory products early after treatment. This early effect likely underlies the delayed anti-inflammatory and anti-hypersensitivity effects of perineural clonidine in this setting.

Adrenergic alpha-Agonists↗

PubMed2006

Chronic activation of spinal adenosine A1 receptors results in hypersensitivity.

Spinally administered adenosine reduces hypersensitivity in animals and humans with nerve injury, but also causes transient pain in humans and reduces tonic inhibition in spinal neurons. Nerve injury results in increased tonic spinal cord adenosine A1 receptor activation, consistent with a role for adenosine to generate hypersensitivity. Here, we demonstrate that chronic intrathecal adenosine induces hypersensitivity in normal animals and that chronic blockade of spinal adenosine A1 receptors by the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine partially prevents nerve injury-induced hypersensitivity. In contrast, chronic blockade of spinal adenosine A1 receptors failed to reduce increased tonic G-protein signaling in the spinal cord after nerve injury. These data support a role for chronic adenosine A1 receptor stimulation after nerve injury to result in hypersensitivity.

Adenosine↗

PubMed2006

Perineural clonidine reduces p38 mitogen-activated protein kinase activation in sensory neurons.

Perineural injection of clonidine at the site of nerve injury reduces hypersensitivity while simultaneously reducing leukocyte number and cytokine expression and hyperexcitability in sensory neurons. The activation of p38 mitogen-activated protein kinase in sensory neurons contributes to the development and maintenance of inflammatory and neuropathic pain. Here, we tested whether perineural clonidine affected activation of p38 mitogen-activated protein kinase following partial sciatic nerve ligation. Perineural clonidine significantly increased withdrawal threshold and concomitantly reduced phosphorylation of p38 mitogen-activated protein kinase in sensory neurons ipsilateral to injury. Clonidine's effects were blocked by the alpha2-adrenoceptor antagonist, BRL44408. These data suggest that activation of alpha2-adrenoceptors at the site of nerve injury, probably by immune modulation, reduces intracellular signaling in primary afferents that leads to hypersensitivity.

Adrenergic alpha-Agonists↗

PubMed2006

Clonidine maintains intrathecal self-administration in rats following spinal nerve ligation.

Clonidine is approved for spinal administration against neuropathic pain, and reverses both spontaneous and elicited pain in humans following spinal administration. Rodent studies that seek to model pharmacology in pain states have historically relied on reflexive withdrawal from noxious stimuli as the primary endpoint. Drug self-administration studies have face validity in the drug abuse field for modeling drug abuse in humans, however, this methodology has not been applied to address issues related to drug seeking behaviors that may be relevant for other human populations, such as patients with neuropathic pain. Rats without spinal nerve ligation (SNL) failed to acquire intrathecal clonidine self-administration over 10 days of access. Rats were found to self-administer intrathecal infusions of clonidine following SNL in a stable and dose-responsive manner, however, and clonidine was self-administered throughout the day with 66% of total drug intake occurring during the dark cycle. Substitution of clonidine with saline or with clonidine and the alpha2-adrenoceptor antagonist idazoxan resulted in extinction of responding in SNL animals. Food reinforcement was initially decreased in SNL rats self-administering clonidine compared to normal animals, however, tolerance developed to this effect of clonidine in SNL rats after 5 days. These data demonstrate that drug self-administration can be applied to questions other than drug abuse, and provides an additional measure for development of novel therapeutic strategies for chronic pain treatment.

Analgesics↗

PubMed2006

Spinal cord dynorphin expression increases, but does not drive microglial prostaglandin production or mechanical hypersensitivity after incisional surgery in rats.

Spinally released dynorphin contributes to hypersensitivity from nerve injury, inflammation, and sustained morphine treatment, but its role in post-operative pain has not been tested. Intrathecal injection of dynorphin activates cyclooxygenase (COX)-1 and -2 to induce hypersensitivity. Spinal COX-1 expression and activity increase following incisional paw surgery in rats, although the stimulus for this increase is not known. In the current study we tested whether spinal dynorphin expression increases after incisional surgery and induces hypersensitivity in this setting, and whether dynorphin stimulates COX-1 activity in spinal cord microglia. Paw incision resulted in increased prodynorphin immunoreactivity in laminae I, IIo, and V in the L4-L6 spinal cord dorsal horn ipsilateral to surgery. Change in prodynorphin expression did not parallel that of mechanical hypersensitivity. Repeated intrathecal dynorphin A antiserum injection failed to alter mechanical hypersensitivity after incisional surgery, although it was effective against mechanical hypersensitivity following spinal nerve ligation. Paw incision increased COX-1 immunoreactivity in the L4-L6 ipsilateral spinal cord, and these cells were confirmed to be microglia by co-localization with OX-42. Spinal cord microglia in culture expressed COX-1 immunoreactivity and released PGE2, but dynorphin A failed to increase release of PGE2 in these cultures. These results suggest that increased COX-1 expression occurs in spinal cord microglia following incisional surgery. Although prodynorphin immunoreactivity also increases, it likely does not drive COX-1 expression or mechanical hypersensitivity in this setting.

Animals↗

PubMed2006

Spinal glial activation contributes to postoperative mechanical hypersensitivity in the rat.

UNLABELLED: The activation of spinal cord microglia and astrocytes after peripheral nerve injury or inflammation contributes to behavioral hypersensitivity. The contribution of spinal cord glia to mechanical hypersensitivity after hind paw incision has not been investigated previously. Male Sprague-Dawley rats underwent a unilateral plantar hind paw incision, and the development of mechanical hypersensitivity was assessed by using von Frey filaments. The activation of spinal cord microglia and astrocytes was measured 1, 2, 3, and 5 days after hind paw incision by using immunohistochemistry. The glial activation inhibitor, fluorocitrate, was administered intrathecally 24 hours after hind paw incision to determine glial involvement in mechanical hypersensitivity. Hind paw incision induced an activation of spinal astrocytes ipsilateral to incision within 24 hours. Both microglia and astrocytes reached a maximum activation 3 days after hind paw incision. Fluorocitrate produced a dose-dependent reduction in mechanical hypersensitivity when administered 24 hours after hind paw incision. Spinal cord glial activation contributes to the mechanical hypersensitivity that develops after hind paw incision. PERSPECTIVE: Hind paw incision produces mechanical hypersensitivity that can be alleviated with the inhibition of spinal cord glia. Our results suggest that the activation of spinal cord astrocytes within 24 hours of incision contributes to mechanical hypersensitivity. Therefore, spinal cord astrocytes might represent a novel target for the treatment of postoperative pain.

Animals↗

PubMed2006

Age-dependent responses to nerve injury-induced mechanical allodynia.

BACKGROUND: Developmental differences in responses to acute and chronic nerve injury have received minimal attention. This study examines developmental differences in behavioral responses to a proximal (closer to the spinal cord) (L5 and L6 spinal nerve root ligation) or to a more distal (closer to peripheral innervation) (partial sciatic nerve ligation) nerve injury in rats paralleling the infant to young adult human. METHODS: Withdrawal thresholds to von Frey filament testing in the hind paw were determined before and various times after either spinal nerve root ligation or partial sciatic nerve ligation in rats aged 2, 4, and 16 weeks. Control rats of these ages were observed serially without surgery. Times for withdrawal thresholds to mechanical stimuli to return to 80% of that of the hind paw in the control animals were compared among the different ages in the two models. RESULTS: Baseline withdrawal thresholds in younger rats were lower (P < 0.05). In the 2-week-old animals, distal injury partial sciatic nerve ligation did not cause a reduction in withdrawal threshold from baseline. This was different from the spinal nerve root ligation group and the older animals in the partial sciatic nerve ligation group. However, when compared with age-matched control animals, both nerve injuries resulted in reduced withdrawal thresholds (P < 0.05). The resolution of hypersensitivity to mechanical stimulation, as measured by return of threshold to 80% of controls, occurred more quickly in 2-week-old than in 4- and 16-week-old animals in both injury models (P < 0.05). CONCLUSION: These data suggest that resolution of sensitization to A-fiber input occurs more rapidly in young animals. In addition, distal injury has less of a sensitizing effect on A-fiber input than proximal injury in the younger animals. The authors speculate that neuroimmune responses, especially at the site of injury, are developmentally regulated and less likely to produce chronic pain when injury occurs at a young age.

Aging↗

PubMed2006

Perineural clonidine reduces mechanical hypersensitivity and cytokine production in established nerve injury.

BACKGROUND: Partial sciatic nerve ligation (PSNL) produces axonal damage, a local inflammatory response, and wallerian degeneration. Cytokines secreted near the site of nerve injury are thought to play important roles in development and maintenance of central sensitization and neuropathic pain. Injection of clonidine at the site and time of nerve injury slows the development of PSNL-induced hypersensitivity and reduces local cytokine expression by actions on alpha2 adrenoceptors. The current study tested whether clonidine would have a similar effect in established nerve injury. METHODS: Rats underwent unilateral PSNL, and perineural saline, clonidine, or BRL44408 plus clonidine was injected 2 weeks later. Three days after perineural injection, withdrawal threshold to mechanical stimulation of the hind paw ipsilateral and contralateral to PSNL was determined, and tissues were removed for cytokine analysis. RESULTS: PSNL was accompanied by a proinflammatory pattern of cytokine content in neural structures and hypersensitivity ipsilaterally with few changes contralaterally. Perineural clonidine, but not saline, partially reversed the hypersensitivity, accompanied by reduced concentrations of interleukin 6 and interleukin 1beta in the sciatic nerve. The effect of clonidine on hypersensitivity and these cytokines was blocked by the alpha2-adrenoceptor antagonist, BRL44408. CONCLUSIONS: These data suggest that perineural clonidine acts on alpha2 adrenoceptors to reduce hypersensitivity in established nerve injury, likely by an immunomodulatory mechanism, and may be effective in patients in the weeks after nerve injury.

Adrenergic alpha-Agonists↗

PubMed2006

Multifactorial preoperative predictors for postcesarean section pain and analgesic requirement.

BACKGROUND: The study aimed to determine predictive factors for postcesarean pain and analgesia using an assessment of pain threshold and suprathreshold thermal stimuli as well as degree of somatization and anxiety. METHODS: Thirty-four healthy parturients scheduled for cesarean delivery under subarachnoid anesthesia were enrolled. Preoperative thermal pain threshold, intensity, and unpleasantness to heat stimuli applied to arm and lower back, State Trait Anxiety Inventory, and patient expectation for postoperative pain and need for analgesia were assessed. After surgery, overall, resting, and movement pain and analgesic consumption were recorded. Prediction of pain and analgesic use outcomes was made by principal component factor analysis, followed by stepwise linear regression. RESULTS: Resting pain was predicted by two factors, thermal pain and unpleasantness and patient expectation (r2 = 0.26, P < 0.01), evoked pain by thermal pain threshold in the back (r2= 0.20, P < 0.009), composite pain by thermal pain and unpleasantness and preoperative blood pressure (r2 = 0.28, P < 0.008), intraoperative analgesic need by preexisting pain (r2 = 0.22, P < 0.006), recovery room analgesia by thermal pain threshold and State Trait Anxiety Inventory (r2 = 0.27, P < 0.01), and total analgesic need by State Trait Anxiety Inventory (r2 = 0.22, P < 0.01). These models predicted the upper twentieth percentile of composite pain scores and analgesic requirement with sensitivity of 0.71 to 0.80 and specificity of 0.76 to 0.80. CONCLUSIONS: The authors' results suggest a meaningful combination of preoperative patient responses from physical and psychological tests yields a valid multifactorial predictive model for postoperative pain and analgesic requirement with significant improvements over individual predictive variables.

Analgesics↗

PubMed2006

Developmental differences in spinal cyclooxygenase 1 expression after surgical incision.

BACKGROUND: Systemic administration of a cyclooxygenase 1 (COX-1) inhibitor reduces hypersensitivity to mechanical stimuli after incisional paw surgery in 4-week-old, but not 2-week-old, animals. The purpose of the current study was to test whether this developmental difference was reflected by differences in COX-1 expression in the spinal cord after surgery. METHODS: Rats 2 and 4 weeks of age, paralleling infant and child human neurologic developmental stages, were used. A paw incision was made under general anesthesia and the withdrawal thresholds were measured before and after systemic and intrathecal administration of a COX-1 selective inhibitor (SC560). Immunohistochemistry was used to assess COX-1 protein in the spinal cord, and real-time polymerase chain reaction was used to quantify gene expression of COX-1 mRNA. RESULTS: Systemic and intrathecal administration of SC560 produced an increase in withdrawal threshold in the 4-week-old, but not in the 2-week-old, animals. Intrathecal SC560 increased withdrawal thresholds in the 4-week-old animals at a dose 100-fold less than with systemic administration. Cyclooxygenase 1 protein in the spinal cord was increased ipsilateral to surgery in the 4-week-old, but not in the 2-week-old, animals. Cyclooxygenase 1 mRNA was increased in the 4-week-old animals in the spinal cord ipsilateral to surgery relative to the contralateral side of the spinal cord, but not in the 2-week-old animals. CONCLUSIONS: These results suggest that developmental differences in COX-1 expression in the spinal cord likely explain the lack of efficacy of COX-1 inhibitors in the 2-week-old rats. Whether this reflects a deficit in factors that stimulate COX-1 expression or a difference in response to these factors is not addressed, but should similar deficits occur in humans, COX-1 inhibitors may exhibit reduced efficacy in infants.

Age Factors↗

PubMed2006

Uterine cervical afferents in thoracolumbar dorsal root ganglia express transient receptor potential vanilloid type 1 channel and calcitonin gene-related peptide, but not P2X3 receptor and somatostatin.

BACKGROUND: Little is known regarding the phenotype of afferents that innervate the uterine cervix. Chronic estrogen sensitizes uterine cervical afferents to mechanical distension, but whether this reflects changes in afferent neurotransmitter or excitatory ion channel expression is unknown. The authors used immunocytochemistry to characterize uterine cervical afferents and the effects of estrogen on them. METHODS: Fluorogold was injected into the uterine cervix of intact rats (n = 7) and those with ovariectomy alone (n = 9) or with estrogen supplementation (n = 8). Bilateral dorsal root ganglia at T12-L2 were removed and immunostained for transient receptor potential vanilloid type 1 (TRPV1), P2X3 receptor, calcitonin gene-related peptide, and somatostatin. The proportion of fluorogold-traced dorsal root ganglion neurons expressing each of these markers was compared with untraced neurons. RESULTS: Most fluorogold-traced cells were found at L1 (> 55%) and were of small diameter (24 microm). TRPV1 expression was similar between traced and untraced cells, except the estrogen treatment increased TRPV1 expression in traced cells. Calcitonin gene-related peptide expression was greater in traced than in untraced cells, with no effect of experimental treatment. No traced cells expressed the P2X3 receptor or somatostatin, although each of these was present in untraced cells. CONCLUSION: Uterine cervical afferents in the hypogastric nerve express TRPV1, an important nociceptive channel, which may play a role in estrogen-induced sensitization of cervical afferents. High expression of calcitonin gene-related peptide suggests a sensory and efferent role for this peptide. In contrast to other viscera, these afferents do not express somatostatin or P2X3 receptor, indicating a unique phenotype of these C fibers.

Animals↗

PubMed2006

Intrathecal administration of a cylcooxygenase-1, but not a cyclooxygenase-2 inhibitor, reverses the effects of laparotomy on exploratory activity in rats.

Studies of hypersensitivity to mechanical stimuli after incisional surgery suggest that cyclooxygenase (COX)-1, but not COX-2, in the spinal cord participates in postoperative pain. In the current study, we sought to determine the role of COX isoenzymes after laparotomy, examining spontaneous exploratory behavior rather than withdrawal reflexes. Adult male Sprague-Dawley rats underwent subcostal laparotomy surgery under isoflurane anesthesia or received anesthesia without surgery. Exploratory locomotor activity was measured on the first postoperative day after intrathecal injection of dimethyl sulfoxide (vehicle) or COX-1 (SC-560) or COX-2 (NS-398) inhibitors. Laparotomy reduced ambulation, rearing, and rapid small movements (stereotypy) similarly in animals without intrathecal catheters and those receiving intrathecal vehicle control. SC-560 produced a dose-related return to normal exploratory behavior with complete return at doses of 20 mug and larger. In contrast, NS-398 in doses up to 50 mug failed to increase exploratory behavior. These data with exploratory behavior and laparotomy agree with studies with reflexive withdrawal responses after incisional surgery and indicate that COX-1 inhibition reduces pain responses after surgery. Spinal COX-1 inhibition completely restores exploratory activity, including rearing behavior that stretches the abdominal muscles. These data suggest that targeting COX-1 in the spinal cord may produce postoperative analgesia.

Animals↗

PubMed2006

A pain model after gynecologic surgery: the effect of intrathecal and systemic morphine.

BACKGROUND: Despite recent recognition that visceral pain differs from somatic pain in its neurophysiologic basis and treatment modalities, most laboratory studies of postoperative pain use a model of superficial somatic injury, and there is no model of postoperative pain after gynecologic surgery. We describe spontaneous behavior in rats after laparotomy with or without noxious stimulation of the uterus and cervix to more specially address pain after gynecologic surgery. METHODS: Female Sprague-Dawley rats received inhaled anesthesia only, anesthesia with laparotomy, or laparotomy plus 60 min of tonic distension of the lower uterine segment and cervix, followed by video observation of spontaneous behavior. RESULTS: Compared with anesthesia alone, laparotomy decreased some spontaneous behaviors (drinking water, grooming, and exploration). Laparotomy plus uterocervical manipulation further decreased these behaviors and increased abnormal behaviors (licking of the lower abdomen and squashing posture of the pelvis to the floor). Intrathecal and systemic morphine restored spontaneous behavior and reduced abnormal behaviors, with minor differences between routes of administration. CONCLUSIONS: These data suggest that specific behaviors may distinctly reflect somatic and visceral components of postoperative gynecologic pain, and that this model may be used to test novel therapies to relieve pain in this setting.

Administration, Cutaneous↗

PubMed2005

Alpha2-adrenoceptor stimulation transforms immune responses in neuritis and blocks neuritis-induced pain.

Neuropathic pain may be primarily driven by immune responses in peripheral nerves. Peripherally released catecholamines may exacerbate neuropathic pain and also modulate immune responses in a complex and sometimes opposing manner by actions on multiple adrenoceptor subtypes. We showed previously that injection of the alpha2-adrenoceptor agonist clonidine at the site of peripheral nerve injury reduces pain behavior and local tissue pro-inflammatory cytokine content in rats. The current study used a model of acute inflammatory neuritis to test the efficacy and mechanisms of action of alpha2-adrenoceptor stimulation to reduce pain. Zymosan, injected on the sciatic nerve, caused hypersensitivity to mechanical stimuli ipsilateral to injection and contralaterally, so-called mirror image pain. Ipsilateral hypersensitivity was inhibited dose-dependently by perineural injection of clonidine. Zymosan increased leukocyte number at the site of injection 3 d later as well as their content of interleukin 1alpha (IL-1alpha), IL-1beta, and IL-6. Perineural clonidine prevented both the increase in leukocyte number and cytokine expression induced by zymosan. Additionally, clonidine reduced the capacity of leukocytes to express pro-inflammatory cytokines as assessed by treatment of cells ex vivo with lipopolysaccharide, whereas no repression of IL-10 production occurred. Clonidine reduced the number of macrophages and lymphocytes as well as their expression of tumor necrosis factor alpha. All of the effects of clonidine were prevented by coadministration of an alpha2A-adrenoceptor-preferring antagonist. These results suggest that alpha2-adrenoceptor stimulation transforms cytokine gene expression, especially in macrophages and lymphocytes from a pro- to an anti-inflammatory profile in the setting of neuritis, likely relieving neuritis-induced pain by this mechanism.

Adrenergic alpha-Agonists↗

PubMed2005

Spinal nerve ligation increases alpha2-adrenergic receptor G-protein coupling in the spinal cord.

Intrathecal and epidural administration of the alpha2-adrenergic receptor agonist clonidine in humans results in analgesia to both acute nociceptive and chronic neuropathic pain. The potency of clonidine increases with hypersensitivity to mechanical stimuli after nerve injury, although the reasons for this change are unknown. In the present study, we tested the hypothesis that peripheral nerve injury alters either spinal alpha2-adrenergic receptor-mediated G-protein activity or alpha2-adrenergic receptor number. Rats were randomized to left spinal nerve ligation (SNL) or sham surgery. Tactile hypersensitivity in the hindpaw was confirmed and lumbar spinal cords were removed for binding assays. To examine agonist-induced G-protein coupling, [35S]GTP gamma S binding experiments were performed in spinal cord membranes and sections using norepinephrine as an alpha2-adrenergic agonist. SNL was associated with an increase in maximal efficacy, but not potency, of norepinephrine-stimulated [35S]GTP gamma S binding in dorsal horn. SNL had no effect on basal [35S]GTP gamma S binding or on muscarinic cholinergic-stimulated [35S]GTP gamma S binding. [35S]GTP gamma S autoradiography showed that this increase in alpha2-adrenergic-activated G-proteins occurred both ipsilateral and contralateral to SNL surgery. SNL did not alter total alpha2-adrenergic receptor number or affinity to [3H]-rauwolscine binding, and displacement studies with the alpha2A-adrenergic antagonist BRL44408 revealed that most of the binding was associated with the alpha2A-adrenergic subtype. These data suggest that the increased potency of clonidine in neuropathic pain could reflect increased efficiency of G-protein coupling from spinal alpha2-adrenergic receptors.

Adrenergic alpha-Agonists↗

PubMed2005

Spinal noradrenaline transporter inhibition by reboxetine and Xen2174 reduces tactile hypersensitivity after surgery in rats.

Spinal noradrenaline (NA) released in response to noxious stimuli may play an important role in suppression of nociceptive transmission. Here, we investigated the efficacy of a competitive NA transporter inhibitor (reboxetine) and a noncompetitive NA transporter inhibitor peptide, Xen2174, isolated from the Pacific cone snail, to treat tactile hypersensitivity following paw incisional surgery. Male Sprague-Dawley rats were anesthetized, an incision of the plantar aspect of the hind paw was performed, and withdrawal threshold to von Frey filaments near the surgical site determined. Reboxetine (0.5-5 microg) and Xen2174 (0.3-100 microg) increased withdrawal threshold when injected 24h after paw incision, with a peak effect at 15-60 min, for Xen2174, an ED50 value of 0.64 microg. Administration of Xen2174 (3-30 microg) 15 min before incision also reduced hypersensitivity in a dose-dependent manner. Withdrawal threshold after the single 30 microg dose was greater than vehicle control even at 2, 3, and 5 days after incision. Doses <or=30 microg did not alter spontaneous behavior. The anti-hypersensitivity effect of 10 microg of Xen2174 was totally blocked by the alpha2-adrenoceptor antagonist, idazoxan, and partially blocked by the muscarinic antagonist, atropine. These data suggest that selective NA transporter inhibition suppresses post-incisional hypersensitivity through a different mechanism from that of neuropathic pain, since we previously reported that reversal of hypersensitivity by intrathecal clonidine, an alpha2-adrenoceptor agonist, following spinal nerve ligation is completely blocked by intrathecal atropine. Finally, these data suggest that intrathecal administration of Xen2174 at the time of spinal anesthesia might produce postoperative analgesia in humans.

Adrenergic Uptake Inhibitors↗

PubMed2005

Intrathecal morphine and ketorolac analgesia after surgery: comparison of spontaneous and elicited responses in rats.

Pain after surgery results in significant morbidity, and systemic opioids often fail to provide adequate analgesia without marked sedation and respiratory depression. Intrathecal morphine provides better analgesia, but is limited by delayed respiratory depression. Intrathecal injection of the cyclooxygenase inhibitor, ketorolac, has recently entered clinical trials, and the current study examined the interaction between intrathecal morphine and ketorolac to treat postoperative pain. We also sought to compare these treatments on a commonly used assessment of withdrawal threshold and a new assessment of spontaneous behavior after surgery. Male Sprague Dawley rats and underwent hind paw incision or subcostal laparotomy surgery. Intrathecal morphine, ketorolac, or their combination were injected on the first postoperative day, with outcome measure being return to pre-surgery withdrawal threshold with von Frey filament testing of the paw after paw incision, or return to pre-surgery exploratory activity after laparotomy. Intrathecal morphine completely reversed the effects of surgery in both models, but intrathecal ketorolac only partially reversed them. Ketorolac enhanced the potency of morphine several fold in both models, and did so synergistically after paw incision. In all cases drug potency was greater for spontaneous than elicited responses. These data confirm that spinal opioid receptor and cyclooxygenase enzyme inhibition diminish elicited tactile hypersensitivity after surgery, and that they similarly return spontaneous behavior to normal. Differences in drug potency could reflect fundamental differences in outcome measures or in the surgical procedures themselves. These data support combination study of intrathecal morphine and ketorolac for postoperative pain.

Analgesics, Opioid↗