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Comparison of Antinociceptive Effect of Octreotide With Morphine in a Rat Model of Acute Inflammatory Pain

Comparison of Antinociceptive Effect of Octreotide With Morphine in a Rat Model of Acute... Background: Opioids such as morphine are used for treating moderate to severe pain. However, they also produce adverse effects such as nausea, constipation, addiction, and respiratory depression. Thus, other suitable analgesics need to be identified. Somatostatin is an inhibitory neuropeptide that modulates the transmission of pain. However, the half- life of somatostatin is short. In the present study, the antinociceptive effect of octreotide (a stable long-acting analog of somatostatin) was evaluated in rats with acute inflammatory pain. Methods: Sprague Dawley rats (n = 42) were divided into control (n = 6) and carrageenan injected groups (n = 36). The carrageena group was divided into three equal subgroups and treated with saline, morphine (10 mg/kg), and octreotide (3 µg). Rats belonging to each subgroup (n = 12) were again randomly divided into two equal sets. They were subjected to (a) behavioral evaluation of pain (allodynia) and estimation of paw edema, followed by immunohistochemical analysis of the expression of somatostatin type 2 receptor (sst2r) in the spinal cord and (b) estimation of open-field activity. Allodynia and paw edema were measured by von Frey filaments and plethysmometer, respectively, at 3 and 4 h after carrageenan injection. Expression of sst2r was examined after 24 hours, whereas open-field activity was evaluated after 3 hours. Results: In comparison to the saline-treated group, allodynia was partially attenuated by octreotide, though this was almost completely reversed by morphine. Paw edema was unaffected by octreotide, though it was marginally increased by morphine. This was not related to increased activity of rats, following relief from pain. Immunohistochemistry revealed a significant increase in the expression of sst2r in saline-treated rats, but a decrease in other groups. Conclusion: Octreotide has an antinociceptive effect, which was less than morphine. Increased edema following morphine could result from venodilation. Variations in the sst2r expression suggest its involvement in pain modulation at the spinal level. This information may have clinical relevance. Keywords Local, mechanical hypersensitivity, peripheral, somatostatin, somatostatin receptor, rodent Received 14 February 2021; accepted 31 March 2021 effect resulting from disinhibition. In fact, intrathecal Introduction administration of antibody to SST reduces nociception and edema resulting from carrageenan injection in rats. However, Somatostatin (SST), also known as the somatotropin-release contradictory findings have also been reported. inhibitory factor, was first extracted from the hypothalamus SST receptors belong to the G protein-coupled receptor in 1973. SST acts as a paracrine factor, inhibiting the release family and are divided into five subtypes (sst1–5). Among of several hormones such as the growth hormone, insulin, glucagon, and gastrin. It exists as a 14- and 28-amino-acid peptide. Apart from hypothalamus, it is present in the cerebral Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India cortex, amygdala, limbic lobe, periaqueductal gray, and the spinal cord. Within the superficial part of the dorsal horn of Corresponding author: the spinal cord, SST is present within a group of excitatory Subrata Basu Ray, Department of Anatomy, All India Institute of Medical interneurons. Their axon terminals end on inhibitory Sciences, New Delhi 110029, India. interneurons, suggesting that SST could have a pronociceptive E-mail: raysb48@gmail.com Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution- NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-Commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https:// us.sagepub.com/en-us/nam/open-access-at-sage). 2 Annals of Neurosciences these, the sst2A subtype is the most common receptor in the was maintained, and food and water were provided ad libitum. rat brain. This receptor is expressed in the superficial laminae Prior permission was obtained from the Institutional Animal of the dorsal horn, a key area in the transmission of pain Ethics Committee (28/IAEC-1/2017, dated: 10-17-2017). signals. The signal transduction pathway includes the Rats were divided into the control (Group I; n = 6) and inhibition of adenylyl cyclase activity and the closure of carrageenan-injected groups (Group II; n = 36). The voltage-gated calcium channels. However, calcium ion carrageenan group was further randomly divided into three mobilization through phospholipase C activity can occur at equal subgroups (n = 12 per subgroup), which received one of higher concentrations. the following drugs: saline, morphine, or octreotide. Tissue damage is followed by pain, an outcome of direct activation of nociceptors. Nociceptors are sensitized by the varied mix of inflammatory mediators such as prostaglandins Carrageenan Injection in the Paw and bradykinin. In the periphery, SST appears to have a tonic A 2% solution of λ-Carrageenan (Sigma-Aldrich, USA) was inhibitory effect on nociceptors mediated by the sst2A prepared in physiological saline with the use of an receptor. Despite this, the clinical use of SST is limited by ultrasonicator. It was freshly prepared on the day of its extremely short half-life (1–3 min). Instead, its synthetic experiment. A sterile tuberculin syringe was filled with 0.1 analog, octreotide, has a longer half-life (∼120 min), and is mL of the solution. Intraplantar injection was given in the used for treating endocrine tumors arising from the pituitary right hind paw with a 30G needle under isoflurane inhalation and the gut. Both SST and octreotide cross the blood–brain anesthesia. A subcutaneous bleb formed at the site of drug barrier poorly and act peripherally after systemic 12 administration. By the end of two hours, the paw was swollen administration. Similar to SST, octreotide has an 13,14 and edematous. The control group received an equal volume antinociceptive effect in rats. Besides, it also diminished of saline. hyperalgesia arising from antigen-induced arthritis. Also, TT-232, another synthetic analog of SST, inhibited acute somatic and visceral nociception in rodents. Despite this, Drug Administration the role of octreotide in acute inflammatory pain has not been completely delineated. Two hours after carrageenan injection, the following drugs In the current study, the anti-inflammatory and were administered subcutaneously in the gluteal region by a antinociceptive effect of octreotide was investigated in rats tuberculin syringe under light physical restraint—Group IIA: subjected to intraplantar injection of Lambda carrageenan, a saline for injection I.P., Group IIB: morphine sulphate I.P. (10 common method for inducing acute inflammation. mg/kg; Vermor-15, Verve Health Care, New Delhi), and Carrageenans (Iota, Kappa, and Lambda varieties) are Group IIC: octreotide I.P. (3 μg per animal; Wockhardt polysaccharides derived from red seaweeds. Within two to Limited, Mumbai). The dose of 3 µg was selected after a three hours of injection, the affected hind paw becomes preliminary evaluation of different doses of octreotide (3, 10, swollen and edematous, and the rats demonstrate guarding and 30 µg; Figure 1). behavior characterized by the inability to use the paw for weight bearing. The experimental parameters measured were paw swelling (an important feature of inflammation) and Evaluation of Mechanical Allodynia mechanical allodynia by plethysmometer (using the water Testing was done three and four hours after carrageenan displacement method) and von Frey filaments (up-down injection. Rats were placed over a wire mesh platform and method), respectively. This is because SST reportedly has covered with plexiglass cages (16 cm × 16 cm × 16 cm). both anti-inflammatory and antinociceptive effects. The Following acclimatization for 30 min, mechanical allodynia results were compared to morphine, which is a gold standard was evaluated by calibrated nylon von Frey filaments of drug for treating pain. Animals were euthanized after 24 different sizes (3.61, 3.84, 4.08, 4.31, 4.56, 4.74, 4.93, and hours, and immunohistochemical localization of the sst2A 5.18; North Coast Medical Inc., San Jose, USA) using the receptor was performed in the spinal cords. Finally, open- up-down method. The maximum pressure exerted by these field activity was also evaluated after drug administration. filaments varies between 0.4 and 15 g. Testing was performed at the center of the inflamed region. The behavioral end point Methods was reflex withdrawal of the right paw, and the pressure (g) designated as the “withdrawal threshold.” If there was no Experimental Animals withdrawal till the filament size of 5.18, the value was The study was conducted in male Sprague Dawley rats (n = presumed to be 15 g. An algorithm was used to calculate the 42; weight ∼250 g). They were issued from the Central 50% withdrawal threshold (g). Higher values of threshold Animal Facility, AIIMS, New Delhi. Rats were housed at indicate less pain as rats were able to withstand more pressure temperatures between 20°C and 25°C. A 12 h light/dark cycle before withdrawal. Singh and Ray 3 Figure 1. Preliminary study with three different doses of octreotide showed greater antinociceptive effect with the lower dose (3 μg) in comparison to higher doses (10 and 30 μg). Values are expressed as mean ± sem. N = 3 rats/group. mounted onto gelatin-coated slides, dehydrated, cleared, and Estimation of Paw Volume mounted with DPX. Some of the sections were stained with Paw volume was determined after the estimation of allodynia 0.5% Cresyl violet stain for visualization of the Rexed’s at 3 h 15 min and 4 h 15 min after carrageenan injection. laminae. Images were captured using a Nikon Eclipse 80i Digital plethysmometer (Laboratory Enterprises, Nashik, microscope attached to a CCD camera. Quantification of Maharashtra) was used for determining the swelling in the receptor expression (Rexed’s lamina I and outer part of paw (edema). Rats were restrained while the right hind paw lamina II) was done using the Image J software (National was immersed in water to a specified extent (marked with Institutes of Health, Maryland, USA) over the superficial ink). The value represented the paw volume using the water laminae. Three to four sections per rat were used for analysis. displacement method. Nonspecific binding was deducted from the raw values to obtain specific binding. Immunohistochemistry Rats (n = 24 including the control group) were sacrificed 24 Activity Monitoring hours after carrageenan injection. These were anesthetized Open-field activity in the rats (n = 18) was evaluated using with pentobarbital injection (100 mg/kg intraperitoneal) and the Smart Video Tracking software V3.0 (Panlab Harvard then perfused with cold 0.1 M phosphate buffered saline apparatus, Spain). Testing was done three hours after (PBS), followed by cold 4% paraformaldehyde solution by carrageenan injection. A chamber of size 45 cm × 45 cm was the transcardiac route. The lumbar part of the spinal cord used to measure the activity of rats. This chamber was cleaned containing L4 and L5 segments was dissected out and the left with 70% alcohol before and after each experiment. A side scratched with a capillary tube. The tissue was immersed monitoring video camera was fixed on the roof just above the in the fixative for three more days. Then, the tissue was plexiglass chamber. The camera was connected to a computer washed and transferred to the 15% sucrose solution, followed where activity was automatically recorded in the software. by the 30% sucrose solution for 24 hours each at 4°C. Finally, Activity (in inches) was measured in individual rats for 5 min. transverse sections (of 20 μm thickness) of the spinal cord were cut in a cryostat (Leica, Germany) and floated in PBS in multivial trays. These were stored at −20°C. Tissue sections Statistical Analysis were incubated with anti-sst2A receptor polyclonal antibody Statistical analysis was done using the GraphPad Prism (ab134152, Abcam, 1:250) for 48 hours at 4°C and then software (version 8, GraphPad, San Diego, USA). Values are processed for staining by the avidin–biotin complex method expressed as mean ± sem. The values for mechanical allodynia (Vector Labs, Burlingame, USA). The chromogen used was and paw volume were analyzed using one-way analysis of 0.025% diaminobenzidine in PBS. Finally, sections were 4 Annals of Neurosciences variance, followed by Tukey’s multiple comparison test. The Evaluation of Paw Volume quantitative data of immunohistochemical analysis was Edema occurred in all the groups after carrageenan injection analyzed using the same method. Data related to activity was (Figure 3). At 3 h 15 min, swelling in the morphine-treated evaluated using paired t-test. P < .05 was considered group (2 ± 0.16) was significantly higher than the saline (1.48 statistically significant. Individual P-values are indicated in ± 0.15) and octreotide (1.5 ± 0.14) treated groups. However, the figures. at 4 h 15 min, the values for saline (1.9 ± 0.11), morphine (2.4 ± 0.22), and octreotide (2.03 ± 0.15) treated groups were not Results significantly different. Evaluation of Mechanical Allodynia Expression of sst2A Receptor in Spinal Cord Before carrageenan injection, all the rats showed a baseline With reference to Nissl-stained sections, the sst2A expression value of 15 g (Figure 2). Four hours after injection, the was observed over the superficial laminae (Rexed’s lamina I withdrawal threshold in the saline-treated group decreased and outer part of lamina II) of the dorsal horn in the control to 0.7 ± 0.1 g, whereas it was 3.9 ± 0.6 g in the octreotide group (Figure 4). Expression over the remaining part of the group. After three hours, this was lower for the octreotide dorsal horn was comparatively less. Across the mediolateral group (2.86 ± 0.4 g). The morphine-treated group showed extent, a higher expression was observed toward the lateral pain (14 ± 0.7 g) after three hours and baseline values after part. Expression of sst2A increased after carrageenan injection four hours. The values for morphine- and octreotide-treated in the saline group. Also, this was higher toward the central groups were significantly higher than the saline-treated and lateral parts of the dorsal horn. In the morphine-treated group. Also, values for the morphine-treated group were group, expression was almost absent. However, the octreotide- significantly higher than the octreotide-treated group. treated group showed a diffuse pattern of expression over the superficial laminae, which was higher than that of the morphine-treated group. Image analysis of receptor expression showed an increased expression following carrageenan injection (Figure 5). However, the expression decreased significantly following treatment with morphine. Compared to morphine, the octreotide-treated group showed a higher expression, though this was less than the saline- treated group. Figure 2. Comparison of antinociceptive effect of octreotide with morphine in the carrageenan-induced acute inflammatory pain model in rats. Basal values for all the three groups (before carrageenan injection) were 15 g. Following inflammation, saline- treated rats showed acute nociception as evident from the decreased values of withdrawal threshold. This was reversed by morphine at both 3 h and 4 h compared to saline (Φ). Octreotide partially reversed the nociception as observed from the higher values of withdrawal threshold (#). Also, values for the morphine group were higher than the octreotide group (*). P < .05, #; Figure 3. Paw edema following carrageenan injection. It was higher P < .001, Φ Φ Φ/***/###. Values are expressed as mean ± sem. in the morphine-treated group compared to others at 3 h. N = 6 per group. P < .05, Φ/*. Values are expressed as mean ± sem. N = 6 per group. Singh and Ray 5 Figure 4. (A) Nissl-stained section of the spinal cord dorsal horn showing the arrangement of cell bodies of neurons and glia over the superficial laminae (Rexed’s laminae I and II; the dashed line separates medial [m] and lateral [l] half). (B) The control group (without carrageenaninjection) showed the expression of sst2A receptor over lamina I and outer part of lamina II, particularly in the lateral half (arrow). (C) 24 hours after carrageenan injection, receptor expression increased over lamina I and lamina II (outer). Again, a higher expression was observed in the lateral half (arrow). (D) After morphine, a washed-out appearance was noted corresponding to a decrease in expression, likely because of the internalization of the receptors. (E) However, after octreotide, an increased expression, compared to the morphine-treated group, was noted over the superficial laminae as well as the remaining part of dorsal horn. Scale bar—200 μm. N = 6 per group. Figure 5. Estimation of sst2A receptor expression over superficial laminae (laminae I and II outer) by the Image J software. There was an increased expression after carrageenan injection in comparison to the control group. Morphine treatment attenuated receptor expression, whereas there was an increased expression after octreotide treatment, compared to morphine. The groups showed a significant difference between each other. P < .001, *** N = 3–4 sections per rat.up. 6 Annals of Neurosciences Figure 6. Evaluation of activity in carrageenan-injected rats following saline, morphine, or octreotide treatment. All the groups showed a decrease compared to baseline values. P < .05, *; P < .01, **. Values are expressed as mean ± sem. N = 6 per group. tonic inhibition over the nociceptors. Downstream of sst2A, Open-Field Activity transient receptor potential vanilloid 1 channels, key receptors Postcarrageenan injection, rats belonging to all the groups for pain, were probably inactivated by octreotide. Notably, (saline, morphine, and octreotide treatment) showed a octreotide binds with full affinity to the sst2A receptor significant decrease in activity (Figure 6). This was not (subnanomolar) in comparison to other receptor subtypes affected by the antinociceptive effect of morphine or octreotide. such as sst5 (low nanomolar). An alternate mechanism could diminish the release of tumor necrosis factor-α from inflammatory cells. Another possibility could be an Discussion inhibitory effect on purinergic signaling. Despite the antinociceptive effect, an anti-inflammatory action was The results of the current study show that acute inflammatory lacking with relation to paw swelling. Previously, systemic pain induced by carrageenan was almost completely reversed octreotide treatment (10 µg/kg) in rats did not affect edema by morphine, though octreotide could only partially reverse it following mustard oil injection in the paw. However, (19% to 26% of the morphine effect). Notably, paw edema was repetitive administration of octreotide can diminish edema. more after morphine treatment (approximately 26% to 36% Unexpectedly, in preliminary experiments, higher doses of more than saline), though this was not significantly different octreotide (10 and 30 µg per rat) did not produce a from the octreotide-treated group. Expression of the sst2A corresponding increase in the antinociceptive effect compared receptor decreased following morphine and octreotide to the 3 µg dose. Swelling in the paw increased after morphine administration (morphine > octreotide). Activity was uniformly treatment. Monitoring the activity of these rats did not decreased in all groups after carrageenan administration. demonstrate an increase in open-field activity, consequent to Carrageenan injection in the paw is followed by a sterile the reversal of allodynia. Presumably, morphine-induced inflammation, associated with redness, swelling, and pain. venodilation at the site of inflammation could be responsible, Since negligible amount of octreotide crosses the blood–brain though this needs confirmation. This is so because a different barrier, it is likely that the observed antinociceptive effect study showed a decrease in edema after morphine treatment. was mediated peripherally at the site of inflammation. The sst2A receptors are expressed over the superficial Morphine produces antinociception by both central and laminae of the dorsal horn. More specifically, these receptors peripheral mechanisms as it crosses the blood–brain barrier. are present in GABAergic interneurons in the dorsal horn of This could account for its higher antinociceptive effect. the spinal cord. Under higher power, immunostaining was Specific SST (e.g., sst2A) receptors are expressed by a found to be mainly confined to the postsynaptic junctions proportion of the primary sensory afferents, which were within these laminae, as reported previously. The presynaptic likely activated by octreotide, leading to the observed arbors containing SST could be from local interneurons as antinociceptive effect. These receptors exert an endogenous Singh and Ray 7 dorsal rhizotomy did not have any effect on its expression. Funding Receptor expression increased following paw inflammation, This research was funded by the intramural research grant from the when evaluated 24 hours after carrageenan injection. A time All India Institute of Medical Sciences, New Delhi, India (F.8-1/ interval of 24 h was considered sufficient for changes to occur UG-1/2019/RS dated 3-10-2019). at the level of the spinal cord following inflammation, though maximum pain and inflammation are observed within three ORCID ID hours after carrageenan injection. Earlier, an increased Perminder Singh https://orcid.org/0000-0002-4445-1079 expression of the receptor was noted following peripheral inflammation. Moreover, this was higher toward the central References and lateral parts of the superficial laminae as was noted in the current study. Nerve fibers originating from the plantar aspect 1. Brazeau P, Vale W, Burgus R, et al. Hypothalamic polypeptide of the paw terminate in an organized manner along the that inhibits the secretion of immunoreactive pituitary growth hormone. Science 1973; 179(4068): 77–79. mediolateral aspect of the spinal cord. The tibial component 2. Viollet C, Lepousez G, Loudes C, et al. 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Comparison of Antinociceptive Effect of Octreotide With Morphine in a Rat Model of Acute Inflammatory Pain

Annals of Neurosciences , Volume OnlineFirst: 1 – Jan 1, 2021

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Abstract

Background: Opioids such as morphine are used for treating moderate to severe pain. However, they also produce adverse effects such as nausea, constipation, addiction, and respiratory depression. Thus, other suitable analgesics need to be identified. Somatostatin is an inhibitory neuropeptide that modulates the transmission of pain. However, the half- life of somatostatin is short. In the present study, the antinociceptive effect of octreotide (a stable long-acting analog of somatostatin) was evaluated in rats with acute inflammatory pain. Methods: Sprague Dawley rats (n = 42) were divided into control (n = 6) and carrageenan injected groups (n = 36). The carrageena group was divided into three equal subgroups and treated with saline, morphine (10 mg/kg), and octreotide (3 µg). Rats belonging to each subgroup (n = 12) were again randomly divided into two equal sets. They were subjected to (a) behavioral evaluation of pain (allodynia) and estimation of paw edema, followed by immunohistochemical analysis of the expression of somatostatin type 2 receptor (sst2r) in the spinal cord and (b) estimation of open-field activity. Allodynia and paw edema were measured by von Frey filaments and plethysmometer, respectively, at 3 and 4 h after carrageenan injection. Expression of sst2r was examined after 24 hours, whereas open-field activity was evaluated after 3 hours. Results: In comparison to the saline-treated group, allodynia was partially attenuated by octreotide, though this was almost completely reversed by morphine. Paw edema was unaffected by octreotide, though it was marginally increased by morphine. This was not related to increased activity of rats, following relief from pain. Immunohistochemistry revealed a significant increase in the expression of sst2r in saline-treated rats, but a decrease in other groups. Conclusion: Octreotide has an antinociceptive effect, which was less than morphine. Increased edema following morphine could result from venodilation. Variations in the sst2r expression suggest its involvement in pain modulation at the spinal level. This information may have clinical relevance. Keywords Local, mechanical hypersensitivity, peripheral, somatostatin, somatostatin receptor, rodent Received 14 February 2021; accepted 31 March 2021 effect resulting from disinhibition. In fact, intrathecal Introduction administration of antibody to SST reduces nociception and edema resulting from carrageenan injection in rats. However, Somatostatin (SST), also known as the somatotropin-release contradictory findings have also been reported. inhibitory factor, was first extracted from the hypothalamus SST receptors belong to the G protein-coupled receptor in 1973. SST acts as a paracrine factor, inhibiting the release family and are divided into five subtypes (sst1–5). Among of several hormones such as the growth hormone, insulin, glucagon, and gastrin. It exists as a 14- and 28-amino-acid peptide. Apart from hypothalamus, it is present in the cerebral Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India cortex, amygdala, limbic lobe, periaqueductal gray, and the spinal cord. Within the superficial part of the dorsal horn of Corresponding author: the spinal cord, SST is present within a group of excitatory Subrata Basu Ray, Department of Anatomy, All India Institute of Medical interneurons. Their axon terminals end on inhibitory Sciences, New Delhi 110029, India. interneurons, suggesting that SST could have a pronociceptive E-mail: raysb48@gmail.com Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution- NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-Commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https:// us.sagepub.com/en-us/nam/open-access-at-sage). 2 Annals of Neurosciences these, the sst2A subtype is the most common receptor in the was maintained, and food and water were provided ad libitum. rat brain. This receptor is expressed in the superficial laminae Prior permission was obtained from the Institutional Animal of the dorsal horn, a key area in the transmission of pain Ethics Committee (28/IAEC-1/2017, dated: 10-17-2017). signals. The signal transduction pathway includes the Rats were divided into the control (Group I; n = 6) and inhibition of adenylyl cyclase activity and the closure of carrageenan-injected groups (Group II; n = 36). The voltage-gated calcium channels. However, calcium ion carrageenan group was further randomly divided into three mobilization through phospholipase C activity can occur at equal subgroups (n = 12 per subgroup), which received one of higher concentrations. the following drugs: saline, morphine, or octreotide. Tissue damage is followed by pain, an outcome of direct activation of nociceptors. Nociceptors are sensitized by the varied mix of inflammatory mediators such as prostaglandins Carrageenan Injection in the Paw and bradykinin. In the periphery, SST appears to have a tonic A 2% solution of λ-Carrageenan (Sigma-Aldrich, USA) was inhibitory effect on nociceptors mediated by the sst2A prepared in physiological saline with the use of an receptor. Despite this, the clinical use of SST is limited by ultrasonicator. It was freshly prepared on the day of its extremely short half-life (1–3 min). Instead, its synthetic experiment. A sterile tuberculin syringe was filled with 0.1 analog, octreotide, has a longer half-life (∼120 min), and is mL of the solution. Intraplantar injection was given in the used for treating endocrine tumors arising from the pituitary right hind paw with a 30G needle under isoflurane inhalation and the gut. Both SST and octreotide cross the blood–brain anesthesia. A subcutaneous bleb formed at the site of drug barrier poorly and act peripherally after systemic 12 administration. By the end of two hours, the paw was swollen administration. Similar to SST, octreotide has an 13,14 and edematous. The control group received an equal volume antinociceptive effect in rats. Besides, it also diminished of saline. hyperalgesia arising from antigen-induced arthritis. Also, TT-232, another synthetic analog of SST, inhibited acute somatic and visceral nociception in rodents. Despite this, Drug Administration the role of octreotide in acute inflammatory pain has not been completely delineated. Two hours after carrageenan injection, the following drugs In the current study, the anti-inflammatory and were administered subcutaneously in the gluteal region by a antinociceptive effect of octreotide was investigated in rats tuberculin syringe under light physical restraint—Group IIA: subjected to intraplantar injection of Lambda carrageenan, a saline for injection I.P., Group IIB: morphine sulphate I.P. (10 common method for inducing acute inflammation. mg/kg; Vermor-15, Verve Health Care, New Delhi), and Carrageenans (Iota, Kappa, and Lambda varieties) are Group IIC: octreotide I.P. (3 μg per animal; Wockhardt polysaccharides derived from red seaweeds. Within two to Limited, Mumbai). The dose of 3 µg was selected after a three hours of injection, the affected hind paw becomes preliminary evaluation of different doses of octreotide (3, 10, swollen and edematous, and the rats demonstrate guarding and 30 µg; Figure 1). behavior characterized by the inability to use the paw for weight bearing. The experimental parameters measured were paw swelling (an important feature of inflammation) and Evaluation of Mechanical Allodynia mechanical allodynia by plethysmometer (using the water Testing was done three and four hours after carrageenan displacement method) and von Frey filaments (up-down injection. Rats were placed over a wire mesh platform and method), respectively. This is because SST reportedly has covered with plexiglass cages (16 cm × 16 cm × 16 cm). both anti-inflammatory and antinociceptive effects. The Following acclimatization for 30 min, mechanical allodynia results were compared to morphine, which is a gold standard was evaluated by calibrated nylon von Frey filaments of drug for treating pain. Animals were euthanized after 24 different sizes (3.61, 3.84, 4.08, 4.31, 4.56, 4.74, 4.93, and hours, and immunohistochemical localization of the sst2A 5.18; North Coast Medical Inc., San Jose, USA) using the receptor was performed in the spinal cords. Finally, open- up-down method. The maximum pressure exerted by these field activity was also evaluated after drug administration. filaments varies between 0.4 and 15 g. Testing was performed at the center of the inflamed region. The behavioral end point Methods was reflex withdrawal of the right paw, and the pressure (g) designated as the “withdrawal threshold.” If there was no Experimental Animals withdrawal till the filament size of 5.18, the value was The study was conducted in male Sprague Dawley rats (n = presumed to be 15 g. An algorithm was used to calculate the 42; weight ∼250 g). They were issued from the Central 50% withdrawal threshold (g). Higher values of threshold Animal Facility, AIIMS, New Delhi. Rats were housed at indicate less pain as rats were able to withstand more pressure temperatures between 20°C and 25°C. A 12 h light/dark cycle before withdrawal. Singh and Ray 3 Figure 1. Preliminary study with three different doses of octreotide showed greater antinociceptive effect with the lower dose (3 μg) in comparison to higher doses (10 and 30 μg). Values are expressed as mean ± sem. N = 3 rats/group. mounted onto gelatin-coated slides, dehydrated, cleared, and Estimation of Paw Volume mounted with DPX. Some of the sections were stained with Paw volume was determined after the estimation of allodynia 0.5% Cresyl violet stain for visualization of the Rexed’s at 3 h 15 min and 4 h 15 min after carrageenan injection. laminae. Images were captured using a Nikon Eclipse 80i Digital plethysmometer (Laboratory Enterprises, Nashik, microscope attached to a CCD camera. Quantification of Maharashtra) was used for determining the swelling in the receptor expression (Rexed’s lamina I and outer part of paw (edema). Rats were restrained while the right hind paw lamina II) was done using the Image J software (National was immersed in water to a specified extent (marked with Institutes of Health, Maryland, USA) over the superficial ink). The value represented the paw volume using the water laminae. Three to four sections per rat were used for analysis. displacement method. Nonspecific binding was deducted from the raw values to obtain specific binding. Immunohistochemistry Rats (n = 24 including the control group) were sacrificed 24 Activity Monitoring hours after carrageenan injection. These were anesthetized Open-field activity in the rats (n = 18) was evaluated using with pentobarbital injection (100 mg/kg intraperitoneal) and the Smart Video Tracking software V3.0 (Panlab Harvard then perfused with cold 0.1 M phosphate buffered saline apparatus, Spain). Testing was done three hours after (PBS), followed by cold 4% paraformaldehyde solution by carrageenan injection. A chamber of size 45 cm × 45 cm was the transcardiac route. The lumbar part of the spinal cord used to measure the activity of rats. This chamber was cleaned containing L4 and L5 segments was dissected out and the left with 70% alcohol before and after each experiment. A side scratched with a capillary tube. The tissue was immersed monitoring video camera was fixed on the roof just above the in the fixative for three more days. Then, the tissue was plexiglass chamber. The camera was connected to a computer washed and transferred to the 15% sucrose solution, followed where activity was automatically recorded in the software. by the 30% sucrose solution for 24 hours each at 4°C. Finally, Activity (in inches) was measured in individual rats for 5 min. transverse sections (of 20 μm thickness) of the spinal cord were cut in a cryostat (Leica, Germany) and floated in PBS in multivial trays. These were stored at −20°C. Tissue sections Statistical Analysis were incubated with anti-sst2A receptor polyclonal antibody Statistical analysis was done using the GraphPad Prism (ab134152, Abcam, 1:250) for 48 hours at 4°C and then software (version 8, GraphPad, San Diego, USA). Values are processed for staining by the avidin–biotin complex method expressed as mean ± sem. The values for mechanical allodynia (Vector Labs, Burlingame, USA). The chromogen used was and paw volume were analyzed using one-way analysis of 0.025% diaminobenzidine in PBS. Finally, sections were 4 Annals of Neurosciences variance, followed by Tukey’s multiple comparison test. The Evaluation of Paw Volume quantitative data of immunohistochemical analysis was Edema occurred in all the groups after carrageenan injection analyzed using the same method. Data related to activity was (Figure 3). At 3 h 15 min, swelling in the morphine-treated evaluated using paired t-test. P < .05 was considered group (2 ± 0.16) was significantly higher than the saline (1.48 statistically significant. Individual P-values are indicated in ± 0.15) and octreotide (1.5 ± 0.14) treated groups. However, the figures. at 4 h 15 min, the values for saline (1.9 ± 0.11), morphine (2.4 ± 0.22), and octreotide (2.03 ± 0.15) treated groups were not Results significantly different. Evaluation of Mechanical Allodynia Expression of sst2A Receptor in Spinal Cord Before carrageenan injection, all the rats showed a baseline With reference to Nissl-stained sections, the sst2A expression value of 15 g (Figure 2). Four hours after injection, the was observed over the superficial laminae (Rexed’s lamina I withdrawal threshold in the saline-treated group decreased and outer part of lamina II) of the dorsal horn in the control to 0.7 ± 0.1 g, whereas it was 3.9 ± 0.6 g in the octreotide group (Figure 4). Expression over the remaining part of the group. After three hours, this was lower for the octreotide dorsal horn was comparatively less. Across the mediolateral group (2.86 ± 0.4 g). The morphine-treated group showed extent, a higher expression was observed toward the lateral pain (14 ± 0.7 g) after three hours and baseline values after part. Expression of sst2A increased after carrageenan injection four hours. The values for morphine- and octreotide-treated in the saline group. Also, this was higher toward the central groups were significantly higher than the saline-treated and lateral parts of the dorsal horn. In the morphine-treated group. Also, values for the morphine-treated group were group, expression was almost absent. However, the octreotide- significantly higher than the octreotide-treated group. treated group showed a diffuse pattern of expression over the superficial laminae, which was higher than that of the morphine-treated group. Image analysis of receptor expression showed an increased expression following carrageenan injection (Figure 5). However, the expression decreased significantly following treatment with morphine. Compared to morphine, the octreotide-treated group showed a higher expression, though this was less than the saline- treated group. Figure 2. Comparison of antinociceptive effect of octreotide with morphine in the carrageenan-induced acute inflammatory pain model in rats. Basal values for all the three groups (before carrageenan injection) were 15 g. Following inflammation, saline- treated rats showed acute nociception as evident from the decreased values of withdrawal threshold. This was reversed by morphine at both 3 h and 4 h compared to saline (Φ). Octreotide partially reversed the nociception as observed from the higher values of withdrawal threshold (#). Also, values for the morphine group were higher than the octreotide group (*). P < .05, #; Figure 3. Paw edema following carrageenan injection. It was higher P < .001, Φ Φ Φ/***/###. Values are expressed as mean ± sem. in the morphine-treated group compared to others at 3 h. N = 6 per group. P < .05, Φ/*. Values are expressed as mean ± sem. N = 6 per group. Singh and Ray 5 Figure 4. (A) Nissl-stained section of the spinal cord dorsal horn showing the arrangement of cell bodies of neurons and glia over the superficial laminae (Rexed’s laminae I and II; the dashed line separates medial [m] and lateral [l] half). (B) The control group (without carrageenaninjection) showed the expression of sst2A receptor over lamina I and outer part of lamina II, particularly in the lateral half (arrow). (C) 24 hours after carrageenan injection, receptor expression increased over lamina I and lamina II (outer). Again, a higher expression was observed in the lateral half (arrow). (D) After morphine, a washed-out appearance was noted corresponding to a decrease in expression, likely because of the internalization of the receptors. (E) However, after octreotide, an increased expression, compared to the morphine-treated group, was noted over the superficial laminae as well as the remaining part of dorsal horn. Scale bar—200 μm. N = 6 per group. Figure 5. Estimation of sst2A receptor expression over superficial laminae (laminae I and II outer) by the Image J software. There was an increased expression after carrageenan injection in comparison to the control group. Morphine treatment attenuated receptor expression, whereas there was an increased expression after octreotide treatment, compared to morphine. The groups showed a significant difference between each other. P < .001, *** N = 3–4 sections per rat.up. 6 Annals of Neurosciences Figure 6. Evaluation of activity in carrageenan-injected rats following saline, morphine, or octreotide treatment. All the groups showed a decrease compared to baseline values. P < .05, *; P < .01, **. Values are expressed as mean ± sem. N = 6 per group. tonic inhibition over the nociceptors. Downstream of sst2A, Open-Field Activity transient receptor potential vanilloid 1 channels, key receptors Postcarrageenan injection, rats belonging to all the groups for pain, were probably inactivated by octreotide. Notably, (saline, morphine, and octreotide treatment) showed a octreotide binds with full affinity to the sst2A receptor significant decrease in activity (Figure 6). This was not (subnanomolar) in comparison to other receptor subtypes affected by the antinociceptive effect of morphine or octreotide. such as sst5 (low nanomolar). An alternate mechanism could diminish the release of tumor necrosis factor-α from inflammatory cells. Another possibility could be an Discussion inhibitory effect on purinergic signaling. Despite the antinociceptive effect, an anti-inflammatory action was The results of the current study show that acute inflammatory lacking with relation to paw swelling. Previously, systemic pain induced by carrageenan was almost completely reversed octreotide treatment (10 µg/kg) in rats did not affect edema by morphine, though octreotide could only partially reverse it following mustard oil injection in the paw. However, (19% to 26% of the morphine effect). Notably, paw edema was repetitive administration of octreotide can diminish edema. more after morphine treatment (approximately 26% to 36% Unexpectedly, in preliminary experiments, higher doses of more than saline), though this was not significantly different octreotide (10 and 30 µg per rat) did not produce a from the octreotide-treated group. Expression of the sst2A corresponding increase in the antinociceptive effect compared receptor decreased following morphine and octreotide to the 3 µg dose. Swelling in the paw increased after morphine administration (morphine > octreotide). Activity was uniformly treatment. Monitoring the activity of these rats did not decreased in all groups after carrageenan administration. demonstrate an increase in open-field activity, consequent to Carrageenan injection in the paw is followed by a sterile the reversal of allodynia. Presumably, morphine-induced inflammation, associated with redness, swelling, and pain. venodilation at the site of inflammation could be responsible, Since negligible amount of octreotide crosses the blood–brain though this needs confirmation. This is so because a different barrier, it is likely that the observed antinociceptive effect study showed a decrease in edema after morphine treatment. was mediated peripherally at the site of inflammation. The sst2A receptors are expressed over the superficial Morphine produces antinociception by both central and laminae of the dorsal horn. More specifically, these receptors peripheral mechanisms as it crosses the blood–brain barrier. are present in GABAergic interneurons in the dorsal horn of This could account for its higher antinociceptive effect. the spinal cord. Under higher power, immunostaining was Specific SST (e.g., sst2A) receptors are expressed by a found to be mainly confined to the postsynaptic junctions proportion of the primary sensory afferents, which were within these laminae, as reported previously. The presynaptic likely activated by octreotide, leading to the observed arbors containing SST could be from local interneurons as antinociceptive effect. These receptors exert an endogenous Singh and Ray 7 dorsal rhizotomy did not have any effect on its expression. Funding Receptor expression increased following paw inflammation, This research was funded by the intramural research grant from the when evaluated 24 hours after carrageenan injection. A time All India Institute of Medical Sciences, New Delhi, India (F.8-1/ interval of 24 h was considered sufficient for changes to occur UG-1/2019/RS dated 3-10-2019). at the level of the spinal cord following inflammation, though maximum pain and inflammation are observed within three ORCID ID hours after carrageenan injection. Earlier, an increased Perminder Singh https://orcid.org/0000-0002-4445-1079 expression of the receptor was noted following peripheral inflammation. Moreover, this was higher toward the central References and lateral parts of the superficial laminae as was noted in the current study. Nerve fibers originating from the plantar aspect 1. Brazeau P, Vale W, Burgus R, et al. Hypothalamic polypeptide of the paw terminate in an organized manner along the that inhibits the secretion of immunoreactive pituitary growth hormone. Science 1973; 179(4068): 77–79. mediolateral aspect of the spinal cord. The tibial component 2. Viollet C, Lepousez G, Loudes C, et al. 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