pregabalin and Peripheral-Nerve-Injuries

The antihypersensitivity actions of gabapentin and pregabalin have been well characterized in a large number of studies, although the underlying mechanisms have yet to be defined. We have been focusing on the supraspinal structure as a possible site for their action and have demonstrated that intracerebroventricular (i.c.v.) administration of gabapentin and pregabalin indeed decreases thermal and mechanical hypersensitivity in a murine chronic pain model involving partial ligation of the sciatic nerve. This novel supraspinally mediated analgesic effect was markedly suppressed by either depletion of central noradrenaline (NA) or blockade of spinal alpha(2)-adrenergic receptors. Moreover, i.c.v. injection of gabapentin and pregabalin increased spinal NA turnover in mice only after peripheral nerve injury. In locus coeruleus (LC) neurons in brainstem slices prepared from mice after peripheral nerve injury, gabapentin reduced the gamma-aminobutyric acid (GABA) type A receptor-mediated inhibitory postsynaptic currents (IPSCs). Glutamate-mediated excitatory synaptic transmission was hardly affected. Moreover, gabapentin did not reduce IPSCs in slices taken from mice given a sham operation. Although gabapentin altered neither the amplitude nor the frequency of miniature IPSCs, it reduced IPSCs together with an increase in the paired-pulse ratio, suggesting that gabapentin acts on the presynaptic GABAergic nerve terminals in the LC. Together, the data suggest that gabapentin presynaptically reduces GABAergic synaptic transmission, thereby removing the inhibitory influence on LC neurons only in neuropathic pain states, leading to activation of the descending noradrenergic system.

Topics: Amines; Analgesics; Animals; Brain; Cyclohexanecarboxylic Acids; Gabapentin; gamma-Aminobutyric Acid; Humans; Mice; Neuralgia; Peripheral Nerve Injuries; Pregabalin; Synaptic Transmission

Exercise is a known trigger of the inhibitory pain modulation system and its analgesic effect is termed exercise-induced hypoalgesia (EIH). Previous studies have demonstrated that rats with deficient analgesic response following exercise develop more significant hypersensitivity following nerve injury compared to rats with substantial analgesic response following exercise.. A rat model of EIH as an indicator of the pain inhibitory system's efficiency was used to explore the association between EIH profiles and the effect of pharmacotherapy on rat's neuropathic pain.. EIH profiles were assessed by evaluating paw responses to mechanical stimuli before and after exercise on a rotating rod. Rats with a reduction of ≤33% in responses were classified as low EIH and those with ≥67% as high EIH. Low and high EIH rats underwent sciatic nerve chronic constriction injury (CCI). Paw responses to mechanical stimuli were measured at baseline, following CCI, and after treatment with diclofenac, duloxetine or pregabalin. In a different group of low and high EIH rats, EIH was measured before and following treatment with the same medications.. Low EIH rats developed more significant hypersensitivity following CCI. Duloxetine and pregabalin successfully reduced hypersensitivity, although significantly more so in low EIH rats. Diclofenac had limited effects, and only on low EIH rats. Four days of duloxetine administration transformed low EIH rats' profiles to high EIH.. The findings of this study suggest that EIH profiles in rats can not only predict the development of hypersensitivity following injury but may also support targeted pharmacological treatment.. Exercise is a known trigger of the inhibitory pain modulation. Rats with deficient analgesic response following exercise develop more significant hypersensitivity following nerve injury. Pain modulation profiles in rats can also support targeted pharmacological treatment; rats with deficient analgesic response following exercise benefit more from treatment with duloxetine and gabapentin. Treatment with duloxetine can improve pain modulation profile.

Topics: Analgesics; Animals; Constriction, Pathologic; Diclofenac; Duloxetine Hydrochloride; Neuralgia; Pain Threshold; Peripheral Nerve Injuries; Pregabalin; Rats

The current study reports the fabrication of co-combination gel using Pregabalin and Withania coagulans fruit extract to validate its effectiveness for neuropathic pain in chronic constriction injury (CCI) rat models. Three topical gels were prepared using Carbopol 934 through a pseudo-ternary phase diagram incorporating the Pregabalin (2.5%), Withania coagulans extract (2%), and co-combination of both Pregabalin (2.5%) and Withania coagulans extract (2%). Gels were characterized. FTIR showed a successful polymeric network of the gel without any interaction. The drug distribution at the molecular level was confirmed by XRD. The AFM images topographically indicated the rough surface of gels with a size range from 0.25 to 330 nm. DSC showed the disappearance of sharp peaks of the drug and extract, showing successful incorporation into the polymeric network of gels. The in vitro drug release of co-combination gel was 73% over 48 h. The mechanism of drug release by combination gel was Higuchi+ fickian with values of n (0.282) and R2 (0.947). An in vivo study for pain assessment via four methods: (i) heat hyperalgesia, (ii) cold allodynia, (iii) mechano-hyperalgesia, and (iv) dynamic mechano-allodynia, confirmed that topical treatment with co-combination gel reduced the pain significantly as indicated by the p value: R1 (p < 0.001), R2 (p < 0.001), R3 (p < 0.015), and R4 (p < 0.0344). The significance order was R2 (****) > R1 (***) > R3 (**) > R4 (*) > R5 (ns).

Topics: Animals; Constriction; Disease Models, Animal; Gels; Hyperalgesia; Neuralgia; Peripheral Nerve Injuries; Plant Extracts; Pregabalin; Rats; Sciatic Nerve

Hematopoietic stem cell transplantation (HSCT) remains an important therapeutic option for many hematologic malignancies. Bone marrow harvesting from an appropriate donor must be conducted for hematopoietic stem cell transplantation (HSCT). Many previous studies show complications of the recipient after hematopoietic stem cell transplantation (HSCT). However, complications of the donor after bone marrow harvesting are rare. We here report a unique case of a patient who developed sacral nerve root injury after bone marrow harvesting.. A 26-year-old man was admitted to our medical center complaining of acute onset painful burning and tingling sensation at the left posterior thigh and calf. He was a bone marrow donor for his brother's bone marrow transplantation. He had underwent a bone marrow harvesting procedure two days before admission as a bone marrow donor, using both posterior superior iliac spine (PSIS) as the puncture site. Pelvic magnetic resonance image (MRI) showed enhancement around the left S2 nerve root in T1 and T2-weighted images. Nerve conduction studies (NCS) revealed normal conduction velocity and amplitude on both lower extremities. Electromyography (EMG) presented abnormal spontaneous activity and neurogenic motor unit potentials on the S2-innervated intrinsic foot muscle and gastrocnemius, soleus muscle on the left. The patient was treated with pregabalin for pain control. The patient was followed up after 3, 6, and 12 months. Neuropathic pain improved to Visual Analogue Scale (VAS) 1, and recovery state was confirmed by re-innervation patterns of motor unit potentials in electromyography.. Bone marrow harvesting is a relatively safe procedure. However, variable complications may occur. Accurate anatomical knowledge and carefulness are required to avoid sacral nerve root injury when performing the bone marrow harvesting procedure.

Topics: Adult; Bone Marrow Transplantation; Electromyography; Hematologic Neoplasms; Humans; Magnetic Resonance Imaging; Male; Mononeuropathies; Peripheral Nerve Injuries; Pregabalin; Tissue and Organ Harvesting; Tissue Donors; Transplant Donor Site; Treatment Outcome

Pregabalin is a first-line agent for neuropathic pain treatment whose abuse liability remains controversial. Surprisingly, studies exploring the reinforcing properties of pregabalin in operant mouse models are missing.. We evaluated the acquisition of operant pregabalin self-administration in mice exposed to a partial sciatic nerve ligation (PSNL) or a sham operation. After surgery, mice were trained in operant boxes to intravenously self-administer pregabalin at 1.5 or 3 mg/kg/inf or saline during 10 days. Thermal and mechanical sensitivity were assessed before and after self-medication, and depressive-like behaviour was evaluated after discontinuation of the treatment.. Partial sciatic nerve ligation and sham-operated mice exposed to pregabalin at 3 mg/kg/inf showed higher active responding compared to mice exposed to saline. The differences in active responding were more robust in nerve-injured than in sham-operated mice. Self-medication at either dose of pregabalin partially inhibited thermal hypersensitivity, whereas only self-medication at 3 mg/kg/inf reduced mechanical sensitivity. Finally, a depressive-like behaviour was revealed after saline treatment in nerve-injured mice, and this emotional manifestation was abolished after pregabalin treatment at the high dose.. Pregabalin showed reinforcing effects both in PSNL and sham-operated mice and attenuated the nociceptive and emotional manifestations of neuropathic pain in mice self-administering this drug. Therefore, pregabalin self-administration was related to neuropathic pain relief, but also to reinforcing properties related to psychotropic drug effects. This study reveals the improvement in nociceptive and emotional manifestations of neuropathic pain after operant pregabalin self-medication in mice and suggests the reinforcing effects of this drug in an operant paradigm.. This study shows that mice with a nerve injury self-administer pregabalin at doses effective reducing nociceptive hypersensitivity and depressive-like behaviour associated with the neuropathic pain model. Interestingly, mice without neuropathy also develop operant self-administration behaviour, suggesting potential abuse liability of this first-line drug for neuropathic pain treatment.

Topics: Analgesics; Animals; Behavior, Animal; Conditioning, Operant; Disease Models, Animal; Hyperalgesia; Male; Mice; Neuralgia; Peripheral Nerve Injuries; Pregabalin; Sciatic Nerve; Self Administration

The objective of this study was to investigate the analgesic effect of a collagen conduit (Neuragen, Integra LifeSciences Corp, Plainsboro, NJ) using duloxetine (Cymbalta, Lilly, Indianapolis, IN) with or without pregabalin (Lyrica, Pfizer, NY) on pain induced by partial sciatic nerve transection in a rat model.. Adult male Sprague-Dawley rats were divided into 5 groups (n = 10 per group): group 1, nerve damage with no treatment; group 2, nerve damage treated with the application of a collagen conduit and saline; group 3, nerve damage treated with the application of a collagen conduit and duloxetine; group 4, nerve damage treated with the application of a collagen conduit and pregabalin; and group 5, nerve damage treated with the application of a collagen conduit and pregabalin plus duloxetine. Pain levels were evaluated by responses to mechanical and thermal stimuli at baseline before and 3 and 7 days after surgery. Interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF) levels were evaluated in blood, sciatic nerve, and dorsal root ganglion samples collected 7 days after surgery.. The group treated with the collagen conduit and pregabalin exhibited markedly less pain 7 days postoperatively in response to mechanical and thermal stimuli compared with the other groups. IL-10 levels were considerably increased in the group treated with pregabalin. The groups treated with a collagen conduit and duloxetine and a combination of pregabalin and duloxetine also exhibited markedly less pain in response to mechanical and thermal stimuli 7 days after surgery compared with the group that had only nerve injury. The decrease in pain using duloxetine was not as robust but was associated with a decrease of TNF-α. The combination of pregabalin and duloxetine resulted in a substantial decrease in IL-6.. Using a collagen conduit and duloxetine, pregabalin, and their combination helped alleviate neuropathic pain. The mechanism of action might be associated, at least in part, to cytokines.

Topics: Analgesics; Animals; Collagen; Drug Therapy, Combination; Duloxetine Hydrochloride; Male; Neuralgia; Pain Measurement; Peripheral Nerve Injuries; Pharmaceutical Vehicles; Pregabalin; Rats; Rats, Sprague-Dawley; Sciatic Nerve

Noxious stimulus-induced analgesia (NSIA) is a type of conditioned pain modulation in rats that has been used to assess endogenous pain control systems. The descending noradrenergic system is involved in NSIA, and nerve injury induces plastic changes of descending noradrenergic neurons. Thus, we hypothesized that nerve injury would affect NSIA strength and that amitriptyline and pregabalin, which often are used for treating neuropathic pain, might further modulate NSIA through effects on the descending noradrenergic system.. We examined the change in NSIA over time after right L5 spinal nerve ligation (SNL) in rats by measuring the contralateral hind paw withdrawal threshold after left forepaw capsaicin injection. In addition, we examined NSIA after 5 daily intraperitoneal injection of amitriptyline or pregabalin. Microdialysis studies were performed to measure noradrenaline levels after left forepaw capsaicin injection in the left spinal dorsal horn in noninjured rats, SNL rats, and SNL rats that had received 5 daily intraperitoneal injections of amitriptyline or pregabalin.. NSIA was dramatically attenuated 5 and 6 weeks after SNL (P < 0.001). The noradrenaline level in the lumbar spinal cord was significantly increased in noninjured rats receiving forepaw injection of capsaicin compared with vehicle injection (P < 0.001), but not in rats 6 weeks after SNL surgery. Five daily intraperitoneal injections of amitriptyline (10 mg/kg/d) or pregabalin (10 mg/kg/d) at 5 weeks after SNL gradually increased the ipsilateral hindpaw withdrawal threshold (P < 0.001). At 6 weeks after SNL, amitriptyline, but not pregabalin, reversed the attenuation of NSIA by SNL (P < 0.001) and increased the spinal noradrenaline level after forepaw injection of capsaicin (P = 0.005).. These data suggest that endogenous analgesia in neuropathic pain states is strongly decreased from a certain time after nerve injury and that amitriptyline reverses the attenuation of endogenous analgesia through effects on the descending noradrenergic system.

Topics: Adrenergic Neurons; Amitriptyline; Analgesics; Animals; Behavior, Animal; Capsaicin; Disease Models, Animal; Microdialysis; Neuralgia; Norepinephrine; Pain Threshold; Peripheral Nerve Injuries; Pregabalin; Rats; Rats, Sprague-Dawley; Reaction Time; Sensory System Agents; Spinal Nerves; Time Factors

Reducing the risk of chronic postoperative pain through preventive analgesia is an attractive therapeutic concept. Because peripheral nerve lesions are a major cause of chronic pain after surgery, we tested in rats whether analgesic treatment with pregabalin (PGB) has the capacity to mitigate the development of persistent neuropathic pain-like behavior. Starting on the day of spared nerve injury or 1week later, we treated rats with a continuous intrathecal infusion of PGB (300 or 900μg/24hours) or vehicle for up to 28days. Rats receiving early PGB treatment had almost normal withdrawal thresholds for punctate mechanical stimuli and were clearly less sensitive to pinprick or cold stimulation. The responses to punctate mechanical and cold stimulation were still reduced for a brief period after the infusion was terminated, but the difference from vehicle-treated rats was minor. Essentially, the analgesic effect of PGB was limited to the duration of the infusion, whether analgesia started at the time of surgery or with a delay of 1week, independently of the length of the treatment. PGB did not suppress the activation of spinal microglia, indicating that analgesia alone does not eliminate certain pain mechanisms even if they depend, at least partially, on nociceptive input. Unexpectedly, intrathecal infusion of PGB did not inhibit the nerve injury-induced accumulation of its binding target, the voltage-gated calcium channel subunit α2δ1, at primary afferent terminals in the spinal cord. Interference with the synaptic trafficking of α2δ1 is not required to achieve analgesia with PGB.

Topics: Analgesics; Animals; Chronic Pain; gamma-Aminobutyric Acid; Injections, Spinal; Male; Pain Measurement; Peripheral Nerve Injuries; Pregabalin; Rats; Rats, Sprague-Dawley; Treatment Outcome

Topics: Analgesics; Animals; Chronic Pain; gamma-Aminobutyric Acid; Male; Pain Measurement; Peripheral Nerve Injuries; Pregabalin

The purpose of the present study was twofold. First to characterize endpoints distinct to the reflexive responses to sensory stimuli typically used in neuropathic pain models. A second aim was to evaluate two clinically approved drugs carbamazepine (Tegretol) and pregabalin (Lyrica) against these endpoints with the purpose to backtranslate from the clinical to preclinical setting. The selected neuropathic pain model was the spared nerve injury (SNI) model and the endpoints were burrowing and measures of paw posture in Sprague Dawley rats. As previously described, SNI surgery produced a robust heightened sensitivity to tactile and thermal (cold) stimuli. SNI surgery also produced robust decreases in burrowing and affected multiple measures of paw position. There was no correlation between magnitude of change in burrowing and sensory allodynia within SNI operated rats. Pregabalin (10-30 mg/kg IP) produced a reliable reversal of both tactile and cold allodynia and also the burrowing deficit, with minimal effect on neurological function evaluated using rotorod, beam walking and open field activity. Pregabalin did not affect any measure of paw position. Pharmacokinetic studies conducted in satellite animals identified plasma levels of pregabalin at the 10 mg/kg IP dose to be equivalent to clinically efficacious levels recorded in neuropathic patients (3-6 μg/ml). In contrast carbamazepine (10-60 mg/kg IP) had only a very modest effect against a reflexive (tactile) measure, and no effect against the burrowing deficit. Carbamazepine also affected various measures of neurological function, complicating interpretation of the reflexive measure. Measurement of burrowing appears to detect a behavioural deficit associated with the SNI model, that may be attenuated by pregabalin but not carbamazepine. Overall the present findings support an advantage of pregabalin over carbamazepine in terms of both efficacy and tolerability which is consistent with clinical experience. The inclusion of additional endpoints beyond traditional reflexive behaviours further supports the value of rodent neuropathic pain models, such as the SNI, as behavioural assays to detect new chemical entities to treat this pain condition.

Topics: Animals; Behavior, Animal; Carbamazepine; Disease Models, Animal; Dose-Response Relationship, Drug; Gait; gamma-Aminobutyric Acid; Hyperalgesia; Male; Motor Activity; Neuralgia; Peripheral Nerve Injuries; Physical Stimulation; Postural Balance; Pregabalin; Rats; Rotarod Performance Test

Topics: Analgesics; Bone Plates; Female; gamma-Aminobutyric Acid; Humans; Middle Aged; Neuroma; Neurosurgical Procedures; Pain; Paresthesia; Peripheral Nerve Injuries; Peripheral Nervous System Neoplasms; Pregabalin; Radial Nerve; Radius Fractures; Ultrasonography