We studied the effect of the intrathecal infusion of baclofen, an agonist of gamma-aminobutyric a... more We studied the effect of the intrathecal infusion of baclofen, an agonist of gamma-aminobutyric acid, on abnormal muscle tone and spasms associated with spinal spasticity, in a randomized double-blind crossover study. Twenty patients with spinal spasticity caused by multiple sclerosis or spinal-cord injury who had had no response to treatment with oral baclofen received an intrathecal infusion of baclofen or saline for three days. The infusions were administered by means of a programmable pump implanted in the lumbar subarachnoid space. Muscle tone decreased in all 20 patients (mean [+/- SD] Ashworth score for rigidity, from 4.0 +/- 1.0 to 1.2 +/- 0.4; P less than 0.0001), and spasms were decreased in 18 of the 19 patients who had spasms (mean [+/- SD] score for spasm frequency, from 3.3 +/- 1.2 to 0.4 +/- 0.8; P less than 0.0005). Tests for motor function, neurologic examination, and assessments by the patients correctly indicated when baclofen was being infused in all cases. All patients were then entered in an open long-term trial of continuous infusion of intrathecal baclofen. During a mean follow-up period of 19.2 months (range, 10 to 33), muscle tone has been maintained within the normal range (mean Ashworth score, 1.0 +/- 0.1) and spasms have been reduced to a level that does not interfere with activities of daily living (mean spasm score, 0.3 +/- 0.6). No drowsiness or confusion occurred, one pump failed, and two catheters became dislodged and had to be replaced. No infections were observed. Our observations suggest that intrathecal baclofen is an effective long-term treatment for spinal spasticity that has not responded to oral baclofen.
With the increase in the number of total knee surgeries being performed, postoperative analgesic ... more With the increase in the number of total knee surgeries being performed, postoperative analgesic management remains a challenge. We used a new animal knee surgery model to characterize pain-related behavior in the rat, and its therapeutic modulation with systemic and intrathecal drug treatment. Rats were anesthetized with isoflurane and an incision was made over the left knee to expose the patella tendon. The tendon was reflected aside and a 1.4-mm diameter, 0.5 mm deep hole was drilled in both the femur and tibia at 2 mm above and below the knee joint, respectively. The holes were filled with dental cement and the wound was closed. Sham surgery animals only had a skin incision. Some animals had previously been implanted with a lumbar intrathecal catheter for drug injection. At 24 h after surgery, animals received the following drugs systemically: i.p. morphine sulfate 0.3-1 mg/kg, i.p. ketorolac 2.5-20 mg/kg, p.o. celecoxib 10-50 mg/kg, i.p. ketamine hydrochloride 2.5-10 mg/kg, i.p. clonidine hydrochloride 25 microg/kg, p.o. pregabablin 10-20 mg/kg, or drug vehicle; or intrathecally: morphine sulfate 0.3-1 microg, ketorolac 4-80 microg, L-745,337 80 microg, pregabalin 15 microg, neostigmine 0.5 microg, or saline vehicle. Pain-related behavior was then assessed by recording exploratory spontaneous activity, in which vertical and horizontal light beam interruptions were automatically recorded to measure rearing activity and ambulation for 60 min. Data were compared using analysis of variance with the Tukey-B post hoc test. The model demonstrated deficits in rearing and ambulation compared with sham skin incision control animals on postsurgery days 1-3. Systemic and intrathecal morphine improved rearing and ambulation, with knee surgery/ morphine rats displaying as much activity as sham skin incision/vehicle animals, whereas knee surgery/vehicle rats showed decreased activity. Systemic ketorolac 20 mg/kg improved rearing and ambulation, with knee surgery/ketorolac rats showing increased activity compared with knee surgery/vehicle animals. Intrathecal ketorolac 4-40 microg did not increase rearing or ambulation, but the 80 microg dose was effective. Other drugs tested, systemically or intrathecally, did not restore activity to normal levels. This study presents a new simple, reproducible rat model to assess function and discomfort after knee surgery, and one that responds to therapeutic interventions. In this knee surgery model, both systemic and intrathecal administration of either morphine or ketorolac caused reversal of the deficits in rearing and ambulatory behavior at 24 h postsurgery.
Neurotrophins play a crucial role in the maintenance, survival and selective vulnerability of var... more Neurotrophins play a crucial role in the maintenance, survival and selective vulnerability of various neuronal populations within the normal and diseased brain. Several families of growth promoting substances have been identified within the central nervous system (CNS) including the superfamily of nerve growth factor related neurotrophin factors, glial derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF). In addition, other non-neuronal growth factors such as fibroblast growth factor (FGF) have also been identified. This article reviews the trophic anatomy of these factors within the CNS. Intraventricular and intraparenchymal injections of exogenous nerve growth factor result in retrograde labeling mainly within the cholinergic basal forebrain. Distribution of brain derived neurotrophic factor (BDNF) following intraventricular injection is minimal due to the binding to the trkB receptor along the ventricular wall. In contrast, intraparenchymal injections of BDNF...
Patients and animals with diabetes exhibit enhanced vulnerability to bacterial surgical infection... more Patients and animals with diabetes exhibit enhanced vulnerability to bacterial surgical infections. Despite multiple retrospective studies demonstrating the benefits associated with glycemic control in reducing bacterial infection after cardiac surgery, there are fewer guidelines on the use of glycemic control for noncardiac surgeries. In the current study, we investigated whether long-term (begun 2 weeks before surgery) or immediate (just before surgery) glycemic controls, continued postoperatively, can reduce surgical site infection in type 1 diabetic-induced rats. Rats were injected with streptozotocin to induce type 1 diabetes. Four groups of animals underwent surgery and thigh muscle Staphylococcus aureus bacteria challenge (1 × 10 colony forming units) at the time of surgery. Group 1 diabetic rats received insulin treatment just before surgery and continued until the end of study (short-term glycemic control group). Group 2 diabetic rats received insulin treatment 2 weeks before surgery and continued until the end of study (long-term glycemic control). Group 3 diabetic rats received no insulin treatment (no glycemic control group). Group 4 nondiabetic rats served as a healthy control group. Rats were euthanized at 3 or 6 days after surgery. Blood glucose and muscle bacterial burden were measured at 3 or 6 days after surgery. Glycemic control was achieved in both long- and short-term insulin-treated diabetic rats. Compared with untreated diabetic rats, the bacterial burden in muscle was significantly lower in both groups of glycemic controlled diabetic rats at 3 (all P < 0.003) and 6 (all P < 0.0001) days after surgery. A short-term glycemic control regimen, initiated just before surgery and bacterial exposure, was as effective in reducing surgical site infection as a long-term glycemic control in type 1 diabetic rats. These data suggest that immediately implementing glycemic control in type 1 diabetic surgical patients before undergoing noncardiac surgery may decrease the risk of infection.
Experiments were performed in rats to determine if the crz-adrenergic agonist tizanidine has an a... more Experiments were performed in rats to determine if the crz-adrenergic agonist tizanidine has an antinociceptive effect when injected intrathecally, and whether the analgesia is accompanied by changes in blood pressure. Rats were chronically implanted with catheters in the lumbar subarachnoid space. Antinociception was evaluated in conscious rats with the tail-flick test. Increasing tizanidine doses produced increases in analgesic efficacy, with 25 gg producing a significant long-lasting antinociception. This tail-flick analgesia was very similar to that produced by clonidine (25 pg) and morphine (8 pg) in peak effect and duration. Doses as high as 250 pg produced only a transient hind limb motor dysfunction in 43% of the animals. Daily injections of 25 pg tizanidine over 5 days produced a decrease in antinociception, with the peak effect at day 5 at 59% of that at day 1. Blood pressure, in rats lightly anesthetized with halothane, was not affected by tizanidine injections up to 250 pg. Tizanidine appears to be a promising non-opiate analgesic for intrathecal usage.
Methods in molecular biology (Clifton, N.J.), 2015
Pain assessment in animal models of osteoarthritis is integral to interpretation of a model's... more Pain assessment in animal models of osteoarthritis is integral to interpretation of a model's utility in representing the clinical condition, and enabling accurate translational medicine. Here we describe two methods for behavioral pain assessments available for use in animal models of experimental osteoarthritic pain: Von Frey filaments and spontaneous activity monitoring.
The duration of nerve block is longer in streptozotocin (STZ)-induced diabetic rats for all local... more The duration of nerve block is longer in streptozotocin (STZ)-induced diabetic rats for all local anesthetics (with and without adjuvants) compared with normal rats. Perioperative glycemic control is currently practiced to reduce adverse events in many at-risk patients, especially in diabetic patients, to prevent neuropathy, poor wound healing, and greater incidence of infection. The aim of this study was to investigate in diabetic rats the importance of glycemic control before peripheral nerve block. To induce diabetes, rats were intravenously injected with a single dose of 50 mg/kg STZ to destroy pancreatic beta cells. Tactile allodynia in response to von Frey filament stimulation of the plantar hind paws was used as the criterion for diabetic neuropathy. Diabetic rats were randomly divided into experimental treatment groups. The continuous glycemic control experiment compared: 3 U/d insulin implant for 14 days, 1.5 U/d insulin implant for 14 days, and placebo treatment. The acute glycemic control experiment compared a single 6U Human Insulin Isophane Suspension (NPH) injection and placebo treatment. Nondiabetic rats received placebo implants or injections. Following treatment, 0.1 mL of 1% lidocaine hydrochloride with 5 μg/mL epinephrine hydrochloride was injected into the left sciatic notch. Animals were then reevaluated at 10-minute intervals for the absence or presence of sensory and motor response. All STZ-injected rats had blood glucose levels greater than 350 mg/dL and tactile allodynia. After insulin implants or injections, diabetic rats had much lower blood glucose levels than diabetic rats with placebo treatment. With both 3 and 1.5 U/d continuous glycemic control, the local anesthetic solution produced a shorter duration of sensory and motor nerve block in insulin-treated diabetic rats compared with placebo-treated diabetic rats, and shorter duration was similar to nondiabetic rats. With 6 U acute glycemic control in diabetic rats, there was no reduction in nerve block duration compared with placebo-treated diabetic rats. With continuous glycemic control in diabetic rats, the duration of sensory and motor nerve block was about 40 minutes shorter than that in the untreated diabetic rats and similar to that of normal rats. However, acute glycemic control did not affect nerve block duration, suggesting that this neuropathy cannot be rapidly reversed.
After peripheral inflammatory stimuli, spinal cord cyclooyxgenase-2 (COX-2) mRNA and protein leve... more After peripheral inflammatory stimuli, spinal cord cyclooyxgenase-2 (COX-2) mRNA and protein levels increase, whereas COX-1 is unchanged. In animal models of inflammatory pain, intrathecal COX-2 selective inhibitors suppress hyperalgesia. However, the role of spinal COX-2 inhibition in postoperative pain is not well elucidated. This study investigates whether a water-soluble COX-2 selective inhibitor, L-745337, can modify allodynic responses in a rat model of postoperative pain. Allodynia was induced in the left plantar hindpaw by surgical incision. Animals then received intrathecal (0-80 micro g) or subcutaneous (0-30 mg/kg) L-745337 coadministered with intrathecal morphine (0-2 nmol). Reduction of mechanical allodynia (increased withdrawal threshold) was quantified with calibrated von Frey hairs. L-745337 alone, whether intrathecal or systemic, had no effect on withdrawal threshold. When intrathecal L-745337 at doses of 40 to 80 micro g was combined with a subthreshold dose (0.5 nmol) of morphine, withdrawal thresholds were increased in a dose-dependent manner. Adding 80 micro g L-745337 to 1 nmol morphine produced an antiallodynic effect greater than that of morphine at twice the dose. Subcutaneous L-745337, up to 30 mg/kg combined with intrathecal morphine resulted in the same antiallodynic response as morphine alone. These results suggest a spinal interaction of COX-2 inhibition with opiate analgesia may allow a reduction of postoperative pain with lower doses of opiate.
A concern for anesthesiologists is whether local anesthetics are more toxic to peripheral nerves ... more A concern for anesthesiologists is whether local anesthetics are more toxic to peripheral nerves in diabetic patients. A previous study in streptozotocin-induced diabetic rats showed that larger doses of lidocaine produce moderate nerve injury after nerve block in normal rats and worse injury in diabetic rats. However, it is not clear whether a smaller local anesthetic dose that produces negligible nerve fiber damage in normal rats will produce significant nerve damage in diabetic rats and if adding adjuvant drugs modulates this effect. Rats were intravenously injected with 50 mg/kg streptozotocin to induce diabetes (blood glucose levels 9250 mg/dL) and diabetic neuropathy. After waiting 35 days, an injection (0.1 mL) of 1% lidocaine alone, or with 5 kg/mL epinephrine or 7.5 kg/mL clonidine added, or 0.5% ropivacaine alone was performed at the left sciatic notch in both diabetic and nondiabetic rats. The duration of sensory (pin prick) and motor (toe spreading reflex) nerve block in the hind paws was determined.For histologic controls, all rats also received saline vehicle injection into the right sciatic notch. Another group of uninjected rats was used as naive controls. Left and right nerves were removed 2 days after injection and fixed in situ with a 4% glutaraldehyde solution. Myelinated axon profiles suggestive of neuropathy (myelin figures, pale and swollen,or dark-staining axoplasm) were counted and expressed as a percentage of the total number of fibers in each rat sciatic nerve. All streptozotocin-injected rats became diabetic and had pronounced tactile allodynia. All rats had sensory and motor nerve blocks lasting for at least 50 mins after injection of local anesthetic. The duration of sensory and motor nerve block was longer in diabetic rats than in nondiabetic rats for all drug groups tested. None of the sciatic nerves examined showed greater than 3% nerve fiber degeneration. Although lidocaine in diabetic rats did not produce nerve fiber damage,diabetic rats receiving lidocaine/clonidine or ropivacaine had more abnormal myelinated axon profiles than did nondiabetic rats receiving the same drug. The duration of sciatic nerve block with local anesthetics is longer in diabetic compared with nondiabetic rats. A small, but statistically significant, increase in nerve damage occurred in diabetic rats after nerve block with ropivacaine alone or when duration of lidocaine block was extended with clonidine. These findings may have implications for dosing of local anesthetics in diabetic patients undergoing regional analgesia with nerve blocks.
Although retrospective studies show the risk of neurological complications after spinal anesthesi... more Although retrospective studies show the risk of neurological complications after spinal anesthesia with local anesthetics is small in diabetic patients, there is still concern about the safety of different local anesthetics in diabetics undergoing neuroaxial anesthesia. We examined block duration and histology of spinal cord and roots with intrathecal local anesthetics in diabetic rats. Rats were made diabetic with streptozotocin injection. Blood glucose levels confirmed diabetes, and diabetic neuropathy was verified by tactile hypersensitivity. Diabetic and nondiabetic rats received four intrathecal injections at 3-4-day intervals of 0.75% bupivacaine, with/without 100 µg/mL epinephrine; and 2% lidocaine, with/without 100 µg/mL epinephrine, and duration of sensory (pinprick) and motor (toe-spreading reflex) response inhibition recorded. Four days after the last drug injection, histology of spinal cord and roots was performed. All streptozotocin rats became diabetic and had pronounced tactile allodynia. Intrathecal injection of local anesthetics showed longer duration of sensory and motor block in diabetic rats vs nondiabetics. Histology of caudal spinal cord showed no difference in neuropathology between diabetic and nondiabetic rats. Necrotic neurons were not seen in either group, and white-matter pathology involved less than 0.1% of fibers. Histology of the spinal roots also showed no difference in pathology between groups, and pathology involved less than 0.1% of fibers. Neuron somas in the dorsal root ganglia were normal. Duration of local anesthetic spinal block is longer in diabetic animals than in nondiabetics. However, there was no increased pathology of spinal cord, roots, or dorsal root ganglia.
We studied the effect of the intrathecal infusion of baclofen, an agonist of gamma-aminobutyric a... more We studied the effect of the intrathecal infusion of baclofen, an agonist of gamma-aminobutyric acid, on abnormal muscle tone and spasms associated with spinal spasticity, in a randomized double-blind crossover study. Twenty patients with spinal spasticity caused by multiple sclerosis or spinal-cord injury who had had no response to treatment with oral baclofen received an intrathecal infusion of baclofen or saline for three days. The infusions were administered by means of a programmable pump implanted in the lumbar subarachnoid space. Muscle tone decreased in all 20 patients (mean [+/- SD] Ashworth score for rigidity, from 4.0 +/- 1.0 to 1.2 +/- 0.4; P less than 0.0001), and spasms were decreased in 18 of the 19 patients who had spasms (mean [+/- SD] score for spasm frequency, from 3.3 +/- 1.2 to 0.4 +/- 0.8; P less than 0.0005). Tests for motor function, neurologic examination, and assessments by the patients correctly indicated when baclofen was being infused in all cases. All patients were then entered in an open long-term trial of continuous infusion of intrathecal baclofen. During a mean follow-up period of 19.2 months (range, 10 to 33), muscle tone has been maintained within the normal range (mean Ashworth score, 1.0 +/- 0.1) and spasms have been reduced to a level that does not interfere with activities of daily living (mean spasm score, 0.3 +/- 0.6). No drowsiness or confusion occurred, one pump failed, and two catheters became dislodged and had to be replaced. No infections were observed. Our observations suggest that intrathecal baclofen is an effective long-term treatment for spinal spasticity that has not responded to oral baclofen.
Somatostatin is distributed in the substantia gelatinosa in the dorsal horn of the spinal cord, a... more Somatostatin is distributed in the substantia gelatinosa in the dorsal horn of the spinal cord, and its application has been found to produce an inhibitory effect on nociceptive neurons. Although intraspinal administration of somatostatin-14 produces pain relief in patients with cancer and in postoperative patients, its short half-life limits its clinical usefulness. Octreotide, a synthetic analog of somatostatin, is more stable and not been associated with neurodegenerative changes when administered intrathecally in dogs. Intrathecal octreotide provides analgesia without adverse drug effects when administered chronically for cancer pain; however, treatment periods have been limited. This article describes the 5-year clinical course of two patients receiving intrathecal octreotide for severe, intractable nonmalignant pain. Included in this description are the results of blinded, randomized "N of 1" trials conducted in each of these patients.
Injection of GABA-agonist into globus pallidus in patient with Parkinson's d... more Injection of GABA-agonist into globus pallidus in patient with Parkinson's disease. By - Richard D Penn, Jeffrey S Kroin, Andrea Reinkensmeyer, Daniel M Corcos.
The authors present a case of Hallervorden-Spatz disease (HSD) in a 10-year-old boy treated with ... more The authors present a case of Hallervorden-Spatz disease (HSD) in a 10-year-old boy treated with stereotactic pallidotomy for control of severe dystonia. Hallervorden-Spatz disease is a rare type of neuraxonal dystrophy that can be familial or sporadic. This is the first case of HSD reported in the literature in which a pallidotomy was performed. The patient had progressively worsening dystonias and spasms that prevented useful function of his entire right side and eventually threatened his respiratory ability. Pre- and postoperative magnetic resonance images are presented along with electrophysiological recordings made in the globus pallidus at the time of surgery. Functional improvement in the use of the patient's limbs and relief from the painful dystonia were observed. Stereotactic pallidotomy should be considered as a potential treatment in the management of HSD.
We studied the effect of the intrathecal infusion of baclofen, an agonist of gamma-aminobutyric a... more We studied the effect of the intrathecal infusion of baclofen, an agonist of gamma-aminobutyric acid, on abnormal muscle tone and spasms associated with spinal spasticity, in a randomized double-blind crossover study. Twenty patients with spinal spasticity caused by multiple sclerosis or spinal-cord injury who had had no response to treatment with oral baclofen received an intrathecal infusion of baclofen or saline for three days. The infusions were administered by means of a programmable pump implanted in the lumbar subarachnoid space. Muscle tone decreased in all 20 patients (mean [+/- SD] Ashworth score for rigidity, from 4.0 +/- 1.0 to 1.2 +/- 0.4; P less than 0.0001), and spasms were decreased in 18 of the 19 patients who had spasms (mean [+/- SD] score for spasm frequency, from 3.3 +/- 1.2 to 0.4 +/- 0.8; P less than 0.0005). Tests for motor function, neurologic examination, and assessments by the patients correctly indicated when baclofen was being infused in all cases. All patients were then entered in an open long-term trial of continuous infusion of intrathecal baclofen. During a mean follow-up period of 19.2 months (range, 10 to 33), muscle tone has been maintained within the normal range (mean Ashworth score, 1.0 +/- 0.1) and spasms have been reduced to a level that does not interfere with activities of daily living (mean spasm score, 0.3 +/- 0.6). No drowsiness or confusion occurred, one pump failed, and two catheters became dislodged and had to be replaced. No infections were observed. Our observations suggest that intrathecal baclofen is an effective long-term treatment for spinal spasticity that has not responded to oral baclofen.
With the increase in the number of total knee surgeries being performed, postoperative analgesic ... more With the increase in the number of total knee surgeries being performed, postoperative analgesic management remains a challenge. We used a new animal knee surgery model to characterize pain-related behavior in the rat, and its therapeutic modulation with systemic and intrathecal drug treatment. Rats were anesthetized with isoflurane and an incision was made over the left knee to expose the patella tendon. The tendon was reflected aside and a 1.4-mm diameter, 0.5 mm deep hole was drilled in both the femur and tibia at 2 mm above and below the knee joint, respectively. The holes were filled with dental cement and the wound was closed. Sham surgery animals only had a skin incision. Some animals had previously been implanted with a lumbar intrathecal catheter for drug injection. At 24 h after surgery, animals received the following drugs systemically: i.p. morphine sulfate 0.3-1 mg/kg, i.p. ketorolac 2.5-20 mg/kg, p.o. celecoxib 10-50 mg/kg, i.p. ketamine hydrochloride 2.5-10 mg/kg, i.p. clonidine hydrochloride 25 microg/kg, p.o. pregabablin 10-20 mg/kg, or drug vehicle; or intrathecally: morphine sulfate 0.3-1 microg, ketorolac 4-80 microg, L-745,337 80 microg, pregabalin 15 microg, neostigmine 0.5 microg, or saline vehicle. Pain-related behavior was then assessed by recording exploratory spontaneous activity, in which vertical and horizontal light beam interruptions were automatically recorded to measure rearing activity and ambulation for 60 min. Data were compared using analysis of variance with the Tukey-B post hoc test. The model demonstrated deficits in rearing and ambulation compared with sham skin incision control animals on postsurgery days 1-3. Systemic and intrathecal morphine improved rearing and ambulation, with knee surgery/ morphine rats displaying as much activity as sham skin incision/vehicle animals, whereas knee surgery/vehicle rats showed decreased activity. Systemic ketorolac 20 mg/kg improved rearing and ambulation, with knee surgery/ketorolac rats showing increased activity compared with knee surgery/vehicle animals. Intrathecal ketorolac 4-40 microg did not increase rearing or ambulation, but the 80 microg dose was effective. Other drugs tested, systemically or intrathecally, did not restore activity to normal levels. This study presents a new simple, reproducible rat model to assess function and discomfort after knee surgery, and one that responds to therapeutic interventions. In this knee surgery model, both systemic and intrathecal administration of either morphine or ketorolac caused reversal of the deficits in rearing and ambulatory behavior at 24 h postsurgery.
Neurotrophins play a crucial role in the maintenance, survival and selective vulnerability of var... more Neurotrophins play a crucial role in the maintenance, survival and selective vulnerability of various neuronal populations within the normal and diseased brain. Several families of growth promoting substances have been identified within the central nervous system (CNS) including the superfamily of nerve growth factor related neurotrophin factors, glial derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF). In addition, other non-neuronal growth factors such as fibroblast growth factor (FGF) have also been identified. This article reviews the trophic anatomy of these factors within the CNS. Intraventricular and intraparenchymal injections of exogenous nerve growth factor result in retrograde labeling mainly within the cholinergic basal forebrain. Distribution of brain derived neurotrophic factor (BDNF) following intraventricular injection is minimal due to the binding to the trkB receptor along the ventricular wall. In contrast, intraparenchymal injections of BDNF...
Patients and animals with diabetes exhibit enhanced vulnerability to bacterial surgical infection... more Patients and animals with diabetes exhibit enhanced vulnerability to bacterial surgical infections. Despite multiple retrospective studies demonstrating the benefits associated with glycemic control in reducing bacterial infection after cardiac surgery, there are fewer guidelines on the use of glycemic control for noncardiac surgeries. In the current study, we investigated whether long-term (begun 2 weeks before surgery) or immediate (just before surgery) glycemic controls, continued postoperatively, can reduce surgical site infection in type 1 diabetic-induced rats. Rats were injected with streptozotocin to induce type 1 diabetes. Four groups of animals underwent surgery and thigh muscle Staphylococcus aureus bacteria challenge (1 × 10 colony forming units) at the time of surgery. Group 1 diabetic rats received insulin treatment just before surgery and continued until the end of study (short-term glycemic control group). Group 2 diabetic rats received insulin treatment 2 weeks before surgery and continued until the end of study (long-term glycemic control). Group 3 diabetic rats received no insulin treatment (no glycemic control group). Group 4 nondiabetic rats served as a healthy control group. Rats were euthanized at 3 or 6 days after surgery. Blood glucose and muscle bacterial burden were measured at 3 or 6 days after surgery. Glycemic control was achieved in both long- and short-term insulin-treated diabetic rats. Compared with untreated diabetic rats, the bacterial burden in muscle was significantly lower in both groups of glycemic controlled diabetic rats at 3 (all P < 0.003) and 6 (all P < 0.0001) days after surgery. A short-term glycemic control regimen, initiated just before surgery and bacterial exposure, was as effective in reducing surgical site infection as a long-term glycemic control in type 1 diabetic rats. These data suggest that immediately implementing glycemic control in type 1 diabetic surgical patients before undergoing noncardiac surgery may decrease the risk of infection.
Experiments were performed in rats to determine if the crz-adrenergic agonist tizanidine has an a... more Experiments were performed in rats to determine if the crz-adrenergic agonist tizanidine has an antinociceptive effect when injected intrathecally, and whether the analgesia is accompanied by changes in blood pressure. Rats were chronically implanted with catheters in the lumbar subarachnoid space. Antinociception was evaluated in conscious rats with the tail-flick test. Increasing tizanidine doses produced increases in analgesic efficacy, with 25 gg producing a significant long-lasting antinociception. This tail-flick analgesia was very similar to that produced by clonidine (25 pg) and morphine (8 pg) in peak effect and duration. Doses as high as 250 pg produced only a transient hind limb motor dysfunction in 43% of the animals. Daily injections of 25 pg tizanidine over 5 days produced a decrease in antinociception, with the peak effect at day 5 at 59% of that at day 1. Blood pressure, in rats lightly anesthetized with halothane, was not affected by tizanidine injections up to 250 pg. Tizanidine appears to be a promising non-opiate analgesic for intrathecal usage.
Methods in molecular biology (Clifton, N.J.), 2015
Pain assessment in animal models of osteoarthritis is integral to interpretation of a model's... more Pain assessment in animal models of osteoarthritis is integral to interpretation of a model's utility in representing the clinical condition, and enabling accurate translational medicine. Here we describe two methods for behavioral pain assessments available for use in animal models of experimental osteoarthritic pain: Von Frey filaments and spontaneous activity monitoring.
The duration of nerve block is longer in streptozotocin (STZ)-induced diabetic rats for all local... more The duration of nerve block is longer in streptozotocin (STZ)-induced diabetic rats for all local anesthetics (with and without adjuvants) compared with normal rats. Perioperative glycemic control is currently practiced to reduce adverse events in many at-risk patients, especially in diabetic patients, to prevent neuropathy, poor wound healing, and greater incidence of infection. The aim of this study was to investigate in diabetic rats the importance of glycemic control before peripheral nerve block. To induce diabetes, rats were intravenously injected with a single dose of 50 mg/kg STZ to destroy pancreatic beta cells. Tactile allodynia in response to von Frey filament stimulation of the plantar hind paws was used as the criterion for diabetic neuropathy. Diabetic rats were randomly divided into experimental treatment groups. The continuous glycemic control experiment compared: 3 U/d insulin implant for 14 days, 1.5 U/d insulin implant for 14 days, and placebo treatment. The acute glycemic control experiment compared a single 6U Human Insulin Isophane Suspension (NPH) injection and placebo treatment. Nondiabetic rats received placebo implants or injections. Following treatment, 0.1 mL of 1% lidocaine hydrochloride with 5 μg/mL epinephrine hydrochloride was injected into the left sciatic notch. Animals were then reevaluated at 10-minute intervals for the absence or presence of sensory and motor response. All STZ-injected rats had blood glucose levels greater than 350 mg/dL and tactile allodynia. After insulin implants or injections, diabetic rats had much lower blood glucose levels than diabetic rats with placebo treatment. With both 3 and 1.5 U/d continuous glycemic control, the local anesthetic solution produced a shorter duration of sensory and motor nerve block in insulin-treated diabetic rats compared with placebo-treated diabetic rats, and shorter duration was similar to nondiabetic rats. With 6 U acute glycemic control in diabetic rats, there was no reduction in nerve block duration compared with placebo-treated diabetic rats. With continuous glycemic control in diabetic rats, the duration of sensory and motor nerve block was about 40 minutes shorter than that in the untreated diabetic rats and similar to that of normal rats. However, acute glycemic control did not affect nerve block duration, suggesting that this neuropathy cannot be rapidly reversed.
After peripheral inflammatory stimuli, spinal cord cyclooyxgenase-2 (COX-2) mRNA and protein leve... more After peripheral inflammatory stimuli, spinal cord cyclooyxgenase-2 (COX-2) mRNA and protein levels increase, whereas COX-1 is unchanged. In animal models of inflammatory pain, intrathecal COX-2 selective inhibitors suppress hyperalgesia. However, the role of spinal COX-2 inhibition in postoperative pain is not well elucidated. This study investigates whether a water-soluble COX-2 selective inhibitor, L-745337, can modify allodynic responses in a rat model of postoperative pain. Allodynia was induced in the left plantar hindpaw by surgical incision. Animals then received intrathecal (0-80 micro g) or subcutaneous (0-30 mg/kg) L-745337 coadministered with intrathecal morphine (0-2 nmol). Reduction of mechanical allodynia (increased withdrawal threshold) was quantified with calibrated von Frey hairs. L-745337 alone, whether intrathecal or systemic, had no effect on withdrawal threshold. When intrathecal L-745337 at doses of 40 to 80 micro g was combined with a subthreshold dose (0.5 nmol) of morphine, withdrawal thresholds were increased in a dose-dependent manner. Adding 80 micro g L-745337 to 1 nmol morphine produced an antiallodynic effect greater than that of morphine at twice the dose. Subcutaneous L-745337, up to 30 mg/kg combined with intrathecal morphine resulted in the same antiallodynic response as morphine alone. These results suggest a spinal interaction of COX-2 inhibition with opiate analgesia may allow a reduction of postoperative pain with lower doses of opiate.
A concern for anesthesiologists is whether local anesthetics are more toxic to peripheral nerves ... more A concern for anesthesiologists is whether local anesthetics are more toxic to peripheral nerves in diabetic patients. A previous study in streptozotocin-induced diabetic rats showed that larger doses of lidocaine produce moderate nerve injury after nerve block in normal rats and worse injury in diabetic rats. However, it is not clear whether a smaller local anesthetic dose that produces negligible nerve fiber damage in normal rats will produce significant nerve damage in diabetic rats and if adding adjuvant drugs modulates this effect. Rats were intravenously injected with 50 mg/kg streptozotocin to induce diabetes (blood glucose levels 9250 mg/dL) and diabetic neuropathy. After waiting 35 days, an injection (0.1 mL) of 1% lidocaine alone, or with 5 kg/mL epinephrine or 7.5 kg/mL clonidine added, or 0.5% ropivacaine alone was performed at the left sciatic notch in both diabetic and nondiabetic rats. The duration of sensory (pin prick) and motor (toe spreading reflex) nerve block in the hind paws was determined.For histologic controls, all rats also received saline vehicle injection into the right sciatic notch. Another group of uninjected rats was used as naive controls. Left and right nerves were removed 2 days after injection and fixed in situ with a 4% glutaraldehyde solution. Myelinated axon profiles suggestive of neuropathy (myelin figures, pale and swollen,or dark-staining axoplasm) were counted and expressed as a percentage of the total number of fibers in each rat sciatic nerve. All streptozotocin-injected rats became diabetic and had pronounced tactile allodynia. All rats had sensory and motor nerve blocks lasting for at least 50 mins after injection of local anesthetic. The duration of sensory and motor nerve block was longer in diabetic rats than in nondiabetic rats for all drug groups tested. None of the sciatic nerves examined showed greater than 3% nerve fiber degeneration. Although lidocaine in diabetic rats did not produce nerve fiber damage,diabetic rats receiving lidocaine/clonidine or ropivacaine had more abnormal myelinated axon profiles than did nondiabetic rats receiving the same drug. The duration of sciatic nerve block with local anesthetics is longer in diabetic compared with nondiabetic rats. A small, but statistically significant, increase in nerve damage occurred in diabetic rats after nerve block with ropivacaine alone or when duration of lidocaine block was extended with clonidine. These findings may have implications for dosing of local anesthetics in diabetic patients undergoing regional analgesia with nerve blocks.
Although retrospective studies show the risk of neurological complications after spinal anesthesi... more Although retrospective studies show the risk of neurological complications after spinal anesthesia with local anesthetics is small in diabetic patients, there is still concern about the safety of different local anesthetics in diabetics undergoing neuroaxial anesthesia. We examined block duration and histology of spinal cord and roots with intrathecal local anesthetics in diabetic rats. Rats were made diabetic with streptozotocin injection. Blood glucose levels confirmed diabetes, and diabetic neuropathy was verified by tactile hypersensitivity. Diabetic and nondiabetic rats received four intrathecal injections at 3-4-day intervals of 0.75% bupivacaine, with/without 100 µg/mL epinephrine; and 2% lidocaine, with/without 100 µg/mL epinephrine, and duration of sensory (pinprick) and motor (toe-spreading reflex) response inhibition recorded. Four days after the last drug injection, histology of spinal cord and roots was performed. All streptozotocin rats became diabetic and had pronounced tactile allodynia. Intrathecal injection of local anesthetics showed longer duration of sensory and motor block in diabetic rats vs nondiabetics. Histology of caudal spinal cord showed no difference in neuropathology between diabetic and nondiabetic rats. Necrotic neurons were not seen in either group, and white-matter pathology involved less than 0.1% of fibers. Histology of the spinal roots also showed no difference in pathology between groups, and pathology involved less than 0.1% of fibers. Neuron somas in the dorsal root ganglia were normal. Duration of local anesthetic spinal block is longer in diabetic animals than in nondiabetics. However, there was no increased pathology of spinal cord, roots, or dorsal root ganglia.
We studied the effect of the intrathecal infusion of baclofen, an agonist of gamma-aminobutyric a... more We studied the effect of the intrathecal infusion of baclofen, an agonist of gamma-aminobutyric acid, on abnormal muscle tone and spasms associated with spinal spasticity, in a randomized double-blind crossover study. Twenty patients with spinal spasticity caused by multiple sclerosis or spinal-cord injury who had had no response to treatment with oral baclofen received an intrathecal infusion of baclofen or saline for three days. The infusions were administered by means of a programmable pump implanted in the lumbar subarachnoid space. Muscle tone decreased in all 20 patients (mean [+/- SD] Ashworth score for rigidity, from 4.0 +/- 1.0 to 1.2 +/- 0.4; P less than 0.0001), and spasms were decreased in 18 of the 19 patients who had spasms (mean [+/- SD] score for spasm frequency, from 3.3 +/- 1.2 to 0.4 +/- 0.8; P less than 0.0005). Tests for motor function, neurologic examination, and assessments by the patients correctly indicated when baclofen was being infused in all cases. All patients were then entered in an open long-term trial of continuous infusion of intrathecal baclofen. During a mean follow-up period of 19.2 months (range, 10 to 33), muscle tone has been maintained within the normal range (mean Ashworth score, 1.0 +/- 0.1) and spasms have been reduced to a level that does not interfere with activities of daily living (mean spasm score, 0.3 +/- 0.6). No drowsiness or confusion occurred, one pump failed, and two catheters became dislodged and had to be replaced. No infections were observed. Our observations suggest that intrathecal baclofen is an effective long-term treatment for spinal spasticity that has not responded to oral baclofen.
Somatostatin is distributed in the substantia gelatinosa in the dorsal horn of the spinal cord, a... more Somatostatin is distributed in the substantia gelatinosa in the dorsal horn of the spinal cord, and its application has been found to produce an inhibitory effect on nociceptive neurons. Although intraspinal administration of somatostatin-14 produces pain relief in patients with cancer and in postoperative patients, its short half-life limits its clinical usefulness. Octreotide, a synthetic analog of somatostatin, is more stable and not been associated with neurodegenerative changes when administered intrathecally in dogs. Intrathecal octreotide provides analgesia without adverse drug effects when administered chronically for cancer pain; however, treatment periods have been limited. This article describes the 5-year clinical course of two patients receiving intrathecal octreotide for severe, intractable nonmalignant pain. Included in this description are the results of blinded, randomized "N of 1" trials conducted in each of these patients.
Injection of GABA-agonist into globus pallidus in patient with Parkinson's d... more Injection of GABA-agonist into globus pallidus in patient with Parkinson's disease. By - Richard D Penn, Jeffrey S Kroin, Andrea Reinkensmeyer, Daniel M Corcos.
The authors present a case of Hallervorden-Spatz disease (HSD) in a 10-year-old boy treated with ... more The authors present a case of Hallervorden-Spatz disease (HSD) in a 10-year-old boy treated with stereotactic pallidotomy for control of severe dystonia. Hallervorden-Spatz disease is a rare type of neuraxonal dystrophy that can be familial or sporadic. This is the first case of HSD reported in the literature in which a pallidotomy was performed. The patient had progressively worsening dystonias and spasms that prevented useful function of his entire right side and eventually threatened his respiratory ability. Pre- and postoperative magnetic resonance images are presented along with electrophysiological recordings made in the globus pallidus at the time of surgery. Functional improvement in the use of the patient's limbs and relief from the painful dystonia were observed. Stereotactic pallidotomy should be considered as a potential treatment in the management of HSD.
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