Baled Ibrahim Noufal Khalefa


Permanent Lecturer

Qualification: Master

Academic rank: Lecturer

Specialization: علم حيوان - احياء

- Faculty of Education Alawineia

Publications
DISTRIBUTION OF ABO AND RHESUS BLOOD GROUPS AMONG THE POPULATION IN YEFREN CITY, LIBYA
Journal Article

Abstract The knowledge of the distribution of ABO and Rh blood groups is important for the blood bank's successful administration and necessary for the blood transfusion services among the population. The aim of this current study was to determine the distribution of blood groups of ABO and Rh in Yefren City, Libya. The distribution of ABO and Rhesus blood groups showed that the O group was found to be the highest with a percent (45.06%), followed by the A group (31.27%), B (18.62%), and the least distribution was the AB group (5.05%). Furthermore, our results presented Rh donors: Rh positive was 80.46%, and Rh negative was 19.54%. This study probably provided information about the distribution of blood groups through the population in Yefren.

Baled Ibrahim Noufal Khalefa, (06-2025), مجلة جامعة غريان: مجلة جامعة غريان, 31 1-11

Superior control of inflammatory pain by corticotropin-releasing factor receptor 1 via opioid peptides in distinct pain-relevant brain areas
Journal Article

Abstract

Background: Under inflammatory conditions, the activation of corticotropin-releasing factor (CRF) receptor has been shown to inhibit pain through opioid peptide release from immune cells or neurons. CRF's effects on human and animal pain modulation depend, however, on the distribution of its receptor subtypes 1 and 2 (CRF-R1 and CRF-R2) along the neuraxis of pain transmission. The objective of this study is to investigate the respective role of each CRF receptor subtype on centrally administered CRF-induced antinociception during inflammatory pain.

Methods: The present study investigated the role of intracerebroventricular (i.c.v.) CRF receptor agonists on nociception and the contribution of cerebral CRF-R1 and/or CRF-R2 subtypes in an animal model of Freund's complete adjuvant (FCA)-induced hind paw inflammation. Methods used included behavioral experiments, immunofluorescence confocal analysis, and reverse transcriptase-polymerase chain reaction.

Results: Intracerebroventricular, but systemically inactive, doses of CRF elicited potent, dose-dependent antinociceptive effects in inflammatory pain which were significantly antagonized by i.c.v. CRF-R1-selective antagonist NBI 27914 (by approximately 60%) but less by CRF-R2-selective antagonist K41498 (by only 20%). In line with these findings, i.c.v. administration of CRF-R1 agonist stressin I produced superior control of inflammatory pain over CRF-R2 agonist urocortin-2. Intriguingly, i.c.v. opioid antagonist naloxone significantly reversed the CRF as well as CRF-R1 agonist-elicited pain inhibition. Consistent with existing evidence of high CRF concentrations in brain areas such as the thalamus, hypothalamus, locus coeruleus, and periaqueductal gray following its i.c.v. administration, double-immunofluorescence confocal microscopy demonstrated primarily CRF-R1-positive neurons that expressed opioid peptides in these pain-relevant brain areas. Finally, PCR analysis confirmed the predominant expression of the CRF-R1 over CRF-R2 in representative brain areas such as the hypothalamus.

Conclusion: Taken together, these findings suggest that CRF-R1 in opioid-peptide-containing brain areas plays an important role in the modulation of inflammatory pain and may be a useful therapeutic target for inflammatory pain control.

Baled Ibrahim Noufal Khalefa, (06-2022), Journal of Neuroinflammation: Journal of Neuroinflammation, 19 (1), 1-15

Functional and Anatomical Characterization of Corticotropin-Releasing Factor Receptor Subtypes of the Rat Spinal Cord Involved in Somatic Pain Relief
Journal Article
  • Abstract

Corticotropin-releasing factor (CRF) orchestrates our body's response to stressful stimuli. Pain is often stressful and counterbalanced by activation of CRF receptors along the nociceptive pathway, although the involvement of the CRF receptor subtypes 1 and/or 2 (CRF-R1 and CRF-R2, respectively) in CRF-induced analgesia remains controversial. Thus, the aim of the present study was to examine CRF-R1 and CRF-R2 expression within the spinal cord of rats with Freund's complete adjuvant-induced unilateral inflammation of the hind paw using reverse transcriptase polymerase chain reaction, Western blot, radioligand binding, and immunofluorescence confocal analysis. Moreover, the antinociceptive effects of intrathecal (i.t.) CRF were measured by paw pressure algesiometer and their possible antagonism by selective antagonists for CRF-R1 and/or CRF-R2 as well as for opioid receptors. Our results demonstrated a preference for the expression of CRF-R2 over CRF-R1 mRNA, protein, binding sites and immunoreactivity in the dorsal horn of the rat spinal cord. Consistently, CRF as well as CRF-R2 agonists elicited potent dose-dependent antinociceptive effects which were antagonized by the i.t. CRF-R2 selective antagonist K41498, but not by the CRF-R1 selective antagonist NBI35965. In addition, i.t. applied opioid antagonist naloxone dose-dependently abolished the i.t. CRF- as well as CRF-R2 agonist-elicited inhibition of somatic pain. Importantly, double immunofluorescence confocal microscopy of the spinal dorsal horn showed CRF-R2 on enkephalin (ENK)-containing inhibitory interneurons in close opposition of incoming mu-opioid receptor-immunoreactive nociceptive neurons. CRF-R2 was, however, not seen on pre- or on postsynaptic sensory neurons of the spinal cord. Taken together, these findings suggest that i.t. CRF or CRF-R2 agonists inhibit somatic inflammatory pain predominantly through CRF-R2 receptors located on spinal enkephalinergic inhibitory interneurons which finally results in endogenous opioid-mediated pain inhibition.

Baled Ibrahim Noufal Khalefa, (11-2021), Molecular Neurobiology: Springer, 58 (11), 5459-5472

Waist-hip ratio, body mass index and risk of chronic medical condition in women aged 30 years and above: a cross-sectional study
Journal Article

ABSTRACT The present investigation was undertaken with the aim to study the prevalence and relationship of Waist-Hip Ratio (WHR) and Body Mass Index (BMI) with health risk and their associated socio-demographic correlates in the women. The data was collected from 120 women, aged 30 years and above with a mean age of 47.30 ± 13.20 years (range 30 to 88). The cross-sectional study conducted in 2019 among Sabratha residents. The participants were assessed with anthropometric measurements including height, weight, BMI, waist circumference, hip circumference and WHR. Respondents provided information on their socio-demographic details and health conditions. Prevalence of those who were obese, overweight, normal and underweight based on BMI was 40.0 %, 39.2 %, 18.3 % and 2.5 % respectively. Participants aged 45 years and above were more likely to be overweight and obese compared to those aged 30-44 years. Participants who were none educated were more likely to be overweight compared to complete educated. Participants who were overweight were less likely to have heart problems, while participants who were obese were more likely to have heart problems. Prevalence of those who were high, normal and low based on WHR was 65.8 %, 4.2 % and 30.0 % respectively. Participants aged 45 years and above were more likely to have high WHR compared to those aged 30-44 years. Participants who were overweight and those with a higher WHR were more likely to have heart problems. 

Baled Ibrahim Noufal Khalefa, (04-2020), British Journal of Medical and Health Research: British Journal of Medical and Health Research, 7 (4), 52-60

Accessibility of axonal G protein coupled mu-opioid receptors requires conceptual changes of axonal membrane targeting for pain modulation
Journal Article

Abstract

The mechanisms of axonal trafficking and membrane targeting are well established for sodium channels, which are the principle targets for perineurally applied local anaesthetics. However, they have not been thoroughly investigated for G protein coupled receptors such as mu-opioid receptors (MOR). Focusing on these axonal mechanisms, we found that axonal MOR functionality is quite distinct in two different pain states, i.e. hindpaw inflammation and nerve injury. We observed axonal membrane MOR binding and functional G protein coupling exclusively at sites of CCI nerve injury. Moreover at these axonal membrane sites, MOR exhibited extensive co-localization with the membrane proteins SNAP and Na/K-ATPase as well as NGF-dependent enhanced lipid rafts and L1CAM anchoring proteins. Silencing endogenous L1CAM with intrathecal L1CAM specific siRNA, disrupting lipid rafts with the perineurial cholesterol-sequestering agent MβCD, as well as suppressing NGF receptor activation with the perineurial NGF receptor inhibitor K252a abrogated MOR axonal membrane integration, functional coupling, and agonist-elicited antinociception at sites of nerve injury. These findings suggest that local conceptual changes resulting from nerve injury are required for the establishment of functional axonal membrane MOR. Axonal integration and subsequent accessibility of functionally coupled MOR are of great relevance particularly for patients suffering from severe pain due to nerve injury or tumour infiltration.

Baled Ibrahim Noufal Khalefa, (12-2017), Journal of Controlled Release: ELSEVIER, 268 (3), 352-363

Protein kinase C-mediated mu-opioid receptor phosphorylation and desensitization in rats, and its prevention during early diabetes
Journal Article
  • Abstract
  • Painful diabetic neuropathy is associated with impaired opioid analgesia; however, the precise mechanism in sensory neurons remains unclear. This study aimed to identify putative mechanisms involved in modified opioid responsiveness during early streptozotocin-induced diabetes in rats. In this study, we demonstrate that in diabetic animals, impaired peripheral opioid analgesia is associated with a reduction in functional mu-opioid receptor (MOR) G protein coupling. Mu-opioid receptor immunoreactive neurons colocalized with activated forms of protein kinase C (PKC) and with the receptor for advanced glycation end products (RAGE) during streptozotocin-induced diabetes. Moreover, MOR phosphorylation at Thr370 in sensory neurons of diabetic rats, and thus desensitization, was due to RAGE-dependent PKC activation. Importantly, blocking PKC activation using PKC selective inhibitor, silencing RAGE with intrathecal RAGE siRNA, or inhibiting advanced glycation end product (AGE) formation prevented sensory neuron MOR phosphorylation and, consequently, restored MOR G protein coupling and analgesic efficacy. Thus, our findings give the first in vivo evidence of a RAGE-dependent PKC-mediated heterologous MOR phosphorylation and desensitization in sensory neurons under pathological conditions such as diabetic neuropathy. This may unravel putative mechanisms and suggest possible prevention strategies of impaired opioid responsiveness.

Baled Ibrahim Noufal Khalefa, (04-2016), Jouranl Pain: The international Associaton for the study of pain, 157 (4), 910-921

New insights into mechanisms of opioid inhibitory effects on capsaicin-induced TRPV1 activity during painful diabetic neuropathy
Journal Article

Abstract

Painful diabetic neuropathy is a disease of the peripheral sensory neuron with impaired opioid responsiveness. Since μ-opioid receptor (MOR) activation can inhibit the transient receptor potential vanilloid 1 (TRPV1) activity in peripherally sensory neurons, this study investigated the mechanisms of impaired opioid inhibitory effects on capsaicin-induced TRPV1 activity in painful diabetic neuropathy. Intravenous injection of streptozotocin (STZ, 45 mg/kg) in Wistar rats led to a degeneration of insulin producing pancreatic β-cells, elevated blood glucose, and mechanical hypersensitivity (allodynia). In these animals, local morphine's inhibitory effects on capsaicin-induced nocifensive behavior as well as on capsaicin-induced TRPV1 current in dorsal root ganglion cells were significantly impaired. These changes were associated with a loss in MOR but not TRPV1 in peripheral sensory neurons. Intrathecal delivery of nerve growth factor in diabetic animals normalized sensory neuron MOR and subsequently rescued morphine's inhibitory effects on capsaicin-induced TRPV1 activity in vivo and in vitro. These findings identify a loss in functional MOR on sensory neurons as a contributing factor for the impaired opioid inhibitory effects on capsaicin-induced TRPV1 activity during advanced STZ-induced diabetes. Moreover, they support growing evidence of a distinct regulation of opioid responsiveness during various painful states of disease (e.g. arthritis, cancer, neuropathy) and may give novel therapeutic incentives.

Baled Ibrahim Noufal Khalefa, (10-2014), Neuropharmacology: ELSEVIER, 85 142-152

Peripheralantinociceptiveefficacyandpotencyofanovelopioid compound14-O-MeM6SUincomparisontoknownpeptideand non-peptideopioidagonistsinaratmodelof inflammatorypain
Journal Article

Abstract

This study compared the peripheral analgesic effects of a novel opioid agonist 14-O-methylmorphine-6-O-sulfate (14-O-MeM6SU), to that of non-peptide (morphine, fentanyl) and peptide opioid agonists (Met-enkephalin; met-ENK and β-endorphin; β-END) in a model of localized inflammatory pain evoked by intraplantar (i.pl.) Freund's complete adjuvant (FCA). Nociceptive responses to local opioid agonists were measured by pressure paw-withdrawal procedures. In addition, the antinociceptive efficacy and potency of these test compounds in vivo was compared to that in vitro using the rat vas deferens (RVD) bioassay. Intraplantar 14-O-MeM6SU (0.32–2.53 nmol/rat), morphine (14.95–112.15 nmol/rat), fentanyl (0.19–2.36 nmol/rat), met-ENK (0.10–10 nmol/rat) and β-END (0.77–5.00 nmol/rat) dose dependently increased paw pressure thresholds exclusively in inflamed hindpaws. At higher doses analgesic effects were also seen in noninflamed paws for 14-O-MeM6SU, morphine and fentanyl but not for met-ENK or β-END. The maximal possible local analgesic effect (%) measured in inflamed paws was 50.6±2.7, 18.23±1.78, 37.44±2.17, 36.00±1.43, and 40.69±0.91 for 14-O-MeM6SU, morphine, fentanyl, met-ENK and β-END, respectively. Interestingly, i.pl. administered opioid peptides met-ENK and β-END displayed a peripheral analgesic ceiling effect. This local antinociception was antagonized by co-administered opioid antagonist naloxone-methiodide (NAL-M). Similar to the analgesic testing, the RVD showed the following efficacy order of the test compounds: 14-O-MeM6SU>β-END>fentanyl>met-ENK⪢morphine. Taken together, 14-O-MeM6SU was more potent than morphine, fentanyl and met-ENK and β-END and displayed superiority in the maximum antinociceptive effects. The superiority of local antinociceptive effects of 14-O-MeM6SU might be due to both pharmacodynamic and pharmacokinetic factors.

Baled Ibrahim Noufal Khalefa, (08-2013), ELSEVIER: European Journal of Pharmacology, 713 (3), 54-57

Reduced Number, G Protein Coupling, and Antinociceptive Efficacy of Spinal Mu-Opioid Receptors in Diabetic Rats Are Reversed by Nerve Growth Factor
Journal Article

Abstract

This study investigated putative mechanisms of impaired spinal opioid antinociception such as a downregulation of mu-opioid receptor (MOR) number, coupling, and efficacy in rats with advanced (12 weeks) streptozotocin (STZ)-induced diabetes. Intravenous injection of STZ (45 mg/kg) in Wistar rats led to selective degeneration of insulin-producing pancreatic ß-cells, elevated blood glucose, and mechanical hyperalgesia. In these animals, dose-dependent and naloxone-reversible intrathecal fentanyl antinociception was significantly impaired and associated with a loss in MOR immunoreactivity of calcitonin gene-related peptide–immunoreactive (CGRP-IR) sensory nerve terminals, membrane-bound MOR binding sites, and MOR-stimulated G protein coupling within the dorsal horn of the spinal cord. Intrathecal delivery of nerve growth factor (NGF) in diabetic animals normalized spinal MOR number and G protein coupling and rescued spinal fentanyl-induced antinociception. These findings identify for the first time a loss in functional MOR on central terminals of sensory neurons as a contributing factor for the impaired spinal opioid responsiveness during advanced STZ-induced diabetes that can be reversed by NGF. Moreover, they support growing evidence of a distinct regulation of opioid responsiveness during various painful states of disease (eg, arthritis, cancer, neuropathy) and may give novel therapeutic incentives.

Baled Ibrahim Noufal Khalefa, (04-2013), The Journal of Pain: ELSEVIER, 14 (7), 720-730

Rab7 silencing prevents μ-opioid receptor lysosomal targeting and rescues opioid responsiveness to strengthen diabetic neuropathic pain therapy
Journal Article

Abstract

Painful diabetic neuropathy is poorly controlled by analgesics and requires high doses of opioids, triggering side effects and reducing patient quality of life. This study investigated whether enhanced Rab7-mediated lysosomal targeting of peripheral sensory neuron μ-opioid receptors (MORs) is responsible for diminished opioid responsiveness in rats with streptozotocin-induced diabetes. In diabetic animals, significantly impaired peripheral opioid analgesia was associated with a loss in sensory neuron MOR and a reduction in functional MOR G-protein-coupling. In control animals, MORs were retained mainly on the neuronal cell membrane. In contrast, in diabetic rats, they were colocalized with upregulated Rab7 in LampI-positive perinuclear lysosome compartments. Silencing endogenous Rab7 with intrathecal Rab7-siRNA or, indirectly, by reversing nerve growth factor deprivation in peripheral sensory neurons not only prevented MOR targeting to lysosomes, restoring their plasma membrane density, but also rescued opioid responsiveness toward better pain relief. These findings elucidate in vivo the mechanisms by which enhanced Rab7 lysosomal targeting of MORs leads to a loss in opioid antinociception in diabetic neuropathic pain. This is in contrast to peripheral sensory neuron MOR upregulation and antinociception in inflammatory pain, and provides intriguing evidence that regulation of opioid responsiveness varies as a function of pain pathogenesis.

Baled Ibrahim Noufal Khalefa, (12-2012), Diabetes: American Diabetes Association, 62 (4), 1308-1319

Relative contributions of peripheral versus supraspinal or spinal opioid receptors to the antinociception of systemic opioids
Journal Article

Abstract The contribution of supraspinal, spinal or peripheral mu-opioid receptors (MORs) to the overall antinociception of systemic centrally penetrating versus peripherally restricted opioids has not been thoroughly investi gated. Therefore, we examined paw pressure thresholds in Wistar rats with complete Freund’s adjuvant hindpaw inflammation following different doses of intraplantar (i.pl.) as well as intravenous (i.v.) fentanyl (6.25 50 mg/kg), morphine (1–7.5 mg/kg) or loperamide (1–7.5 mg/kg). Antago nism of the i.v. mu-opioid agonists by intracerebroventricular (i.c.v.), intrathecal (i.t.) or i.pl. naloxone-methiodide (NLXM) revealed the rela tive contributions of supraspinal, spinal and peripheral MOR to the overall antinociceptive effects. In parallel, the MOR density at these three levels of pain transmission was assessed by radioligand binding. Antinociceptive effects of i.v. fentanyl and morphine, but not of the peripherally restricted loperamide were two- to threefold greater and longer lasting compared with their i.pl. administration. I.c.v. but not i.pl. NLXM significantly antagonized fentanyl’s and morphine’s antinociception by 70–80%, whereas i.t. NLXM reduced it by 20–30%. In contrast, antinociception of i.v. loperamide was abolished by i.pl. but not by i.c.v. or i.t. NLXM. In parallel, a respective 32- and sixfold higher MOR density in supraspinal and spinal versus peripheral sensory neurons was detected. In conclusion, in comparison with supraspinal and spinal opioid receptors, peripheral opioid receptors do not significantly contribute to the antinociception of systemic fentanyl and morphine during inflammatory pain. Antinocicep tion of their i.v. administration was superior over both i.v and i.pl. lopera mide, acting exclusively via peripheral MOR. These findings may guide the future development of novel peripherally restricted opioids.

Baled Ibrahim Noufal Khalefa, (10-2011), European Federation of International Association for the Study of Pain Chapters: European Journal of Pain, 16 (5), 690-705

IMPAIRED OPIOID RECEPTOR EXPRESSION, COUPLING AND EFFICACY IN SPINAL CORD SENSORY NEURONS OF RATS WITH STREPTOZOTOCIN-INDUCED DIABETIC NEUROPATHIC PAIN
Conference paper

 Background and Aims: Painful diabetic neuropathy is a peripheral sensory neuron disease, is difficult to treat and is known to be less susceptible to opioid analgesics. In diabetic neuropathy little is known so far about alterations in mu-opioid receptor (MOR) expression, coupling and efficacy of sensory neurons within the spinal cord of diabetic neuropathy. Therefore, the aim of this study was to investigate the changes in MOR expression, signaling and function of sensory neurons at spinal cord level in streptozotocin induced diabetic rats. In addition, it is examined whether i.t. NGF treatment will restore the MOR expression and G-protein coupling and consequently will rescue the deficit in peripheral fentanyl induced analgesia of diabetic rats.

Baled Ibrahim Noufal Khalefa, (09-2011), European Journal of Pain Supplements: Conference: European Journal of Pain Supplements, 104-104

IMPAIRED OPIOID RESPONSIVENESS FOLLOWING DIABETIC NEUROPATHIC PAIN IS DUE TO ENHANCED RAB7-MEDIATED LYSOSOMAL DEGRADATION OF SENSORY NEURON MU-OPIOID RECEPTORS
Conference paper
  • Background and Aims: Loss in the antinociceptive efficacy of systemic, spinal, and supraspinal administration of opioids has been reported in rats with diabetic neuropathic pain. Recent studies investigated alterations in opioid receptor expression and signaling at the spinal level, however, results were conflicting. Since diabetic neuropathy is primarily a disease of the peripheral sensory neuron, this study aimed at investigating alterations of mu-opioid responsiveness during the development of streptozotocin-induced diabetic neuropathic pain in rats.

Baled Ibrahim Noufal Khalefa, (09-2011), European Journal of Pain Supplements: Conference: European Journal of Pain Supplements,, 53-53

SUPERIOR ANTINOCICEPTION OF CENTRALLY PENETRATING OPIOIDS FENTANYL AND MORPHINE OVER THE PERIPHERALLY RESTRICTED OPIOID LOPERAMIDE IN PAIN MODULATION
Conference paper

Background and Aims: The contribution of supraspinal, spinal or peripheral opioid receptors to the overall antinociceptive effects of centrally penetrating versus peripherally restricted opioids is still a matter of debate. Therefore, we examined the antinociceptive effects and its antagonism by intracerebroventricular, intrathecal or intraplantar naloxone methiodide of systemic fentanyl and morphine versus loperamide in relation to the density of mu-opioid receptors (MOR) at the three levels of pain transmission.

Baled Ibrahim Noufal Khalefa, (09-2011), European Journal of Pain Supplements: Conference: European Journal of Pain Supplements,, 90-90

FUNCTIONAL AND ANATOMICAL CHARACTERIZATION OF CORTICOTROPIN-RELEASING FACTOR RECEPTOR SUBTYPES OF RAT SPINAL CORD INVOLVED IN THE MODULATION OF INFLAMMATORY PAIN
Conference paper

 Background and Aims: Visceral pain seems to be attenuated by intrathecal (i.t.) application of corticotropin-releasing factor (CRF) receptor antagonists. In contrast, i.t. CRF elicits inhibition of somatic pain that is reversed by the opioid antagonist naloxone. Previous studies have identified CRFR1 and more predominantly CRFR2 receptors within the dorsal horn of the spinal cord. At present it is unclear to which proportion each CRF receptor subtype contributes to the modulation of inflammatory somatic pain and on which opioid containing neuron population it is located.

Baled Ibrahim Noufal Khalefa, (09-2011), European Journal of Pain Supplements: Conference: European Journal of Pain Supplements,, 204-204

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