minocycline and Cancer-Pain

Anxiety and depression induced by cancer-related pain disturb quality of life and willingness to survive. As a component of the limbic system, the basolateral amygdala (BLA) is critical for processing negative emotions. The reactive microglial engulfment of synapses may promote depression during adolescence. However, whether microglia phagocytose synapses to mediate cancer pain-induced depression remains unclear. The present study established a bone cancer-pain model to investigate the association between dendritic spine synapses and depressive-like behavior and explore the phagocytic function of microglia in the BLA. We found that tumor-bearing mice experienced postoperative pain-related depression, and their BLAs exhibited reactive microglia, as well as phagocytic synapses. The microglial inhibitor minocycline effectively mitigated depressive behavior, synaptic damage, and the phagocytic function of microglia. Our study implicates microglia-mediated synaptic loss in the BLA may act as the pathological basis of depressive-like behavior in bone cancer pain model.

Topics: Animals; Basolateral Nuclear Complex; Bone Neoplasms; Cancer Pain; Mice; Microglia; Minocycline; Quality of Life

Lemairamin (also known as wgx-50), is isolated from the pericarps of the Zanthoxylum plants. As an agonist of α7 nicotinic acetylcholine receptors (α7nAChRs), it can reduce neuroinflammation in Alzheimer's disease. This study evaluated its antinociceptive effects in pain hypersensitivity and explored the underlying mechanisms. The data showed that subcutaneous lemairamin injection dose-dependently inhibited formalin-induced tonic pain but not acute nociception in mice and rats, while intrathecal lemairamin injection also dose-dependently produced mechanical antiallodynia in the ipsilateral hindpaws of neuropathic and bone cancer pain rats without affecting mechanical thresholds in the contralateral hindpaws. Multiple bi-daily lemairamin injections for 7 days did not induce mechanical antiallodynic tolerance in neuropathic rats. Moreover, the antinociceptive effects of lemairamin in formalin-induced tonic pain and mechanical antiallodynia in neuropathic pain were suppressed by the α7nAChR antagonist methyllycaconitine. In an α7nAChR antagonist-reversible manner, intrathecal lemairamin also stimulated spinal expression of IL-10 and β-endorphin, while lemairamin treatment induced IL-10 and β-endorphin expression in primary spinal microglial cells. In addition, intrathecal injection of a microglial activation inhibitor minocycline, anti-IL-10 antibody, anti-β-endorphin antiserum or μ-opioid receptor-preferred antagonist naloxone was all able to block lemairamin-induced mechanical antiallodynia in neuropathic pain. These data demonstrated that lemairamin could produce antinociception in pain hypersensitivity through the spinal IL-10/β-endorphin pathway following α7nAChR activation.

Topics: Aconitine; Acrylamides; alpha7 Nicotinic Acetylcholine Receptor; Analgesics; Animals; beta-Endorphin; Cancer Pain; Female; Formaldehyde; Hyperalgesia; Injections, Spinal; Interleukin-10; Male; Mice; Microglia; Minocycline; Naloxone; Neuralgia; Rats; Rats, Wistar; Spinal Cord; Zanthoxylum

Pain and depression are highly prevalent symptoms in cancer patients. They tend to occur simultaneously and affect each other and share biological pathways and neurotransmitters. In this study, we investigated the roles of microglia in the hippocampus in the comorbidity of bone cancer pain and depressive-like behaviors in an animal model of bone cancer pain.. Bone cancer pain was induced by injection of Walker 256 mammary gland carcinoma cells into the tibia of rats. The effects of intracerebroventricular administration of microglia inhibitor minocycline were examined.. Carcinoma intratibia injection caused comorbidity of mechanical allodynia and depressive-like behaviors in rats and activation of microglia in the hippocampus. Both mechanical allodynia and depressive-like behaviors were attenuated by minocycline. Enzyme-linked immunosorbent assay analysis showed that the enhanced expressions of M1 microglia marker (CD 86) and the proinflammatory cytokines tumor necrosis factor-α and interleukin-1β in the hippocampus of cancer-bearing rats were decreased by minocycline. On the other hand, minocycline also increased the expressions of M2 microglia marker (MRC1) and anti-inflammatory cytokine interleukin-10.. The results suggest that the activation of microglia in the hippocampus plays an important role in the development of pain and depressive-like behaviors in bone cancer condition.

Topics: Animals; Bone Neoplasms; Cancer Pain; Depression; Female; Hippocampus; Inflammation Mediators; Injections, Intraventricular; Microglia; Minocycline; Rats; Rats, Wistar

Activation of spinal cord microglia is crucial for the development of bone cancer pain (BCP). The essential signal between neuronal excitability and microglial activation is not fully understood. In the present study, carcinoma implantation into tibia was used to induce BCP and RNAi-lentivirus was injected into spinal cord to knock down C1, C2 or C3 of complement cascade. We showed that C1, C2 and C3 co-localized in the same neurons and increased in cancer-bearing rats along with microglial activation. Knocked down of C1, C2 or C3 inhibited microglial activation and prevented the development of cancer-induced bone pain. Intrathecal administration of either minocycline (an inhibitor of microglial activity) to inhibit the activation of microglia or compstatin (a C3-targeted complement inhibitor) to block the complement cascade reversed cancer induced bone pain. Further study indicated that neuronal complement promoted the activation of microglia via complement 3 receptor (C3R). In the in vitro experiments, the proliferation of microglia was enhanced by the activation product of C3 (iC3b), but was inhibited by compstatin. These results indicated that neuronal complement pathway promoted the activation of microglia via C3R and contributed to the development of BCP.

Topics: Animals; Bone Neoplasms; Cancer Pain; Cell Line, Tumor; Complement C3; Female; Hyperalgesia; Macrophage-1 Antigen; Mammary Neoplasms, Experimental; Microglia; Minocycline; Neurons; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Signal Transduction; Spinal Cord; Up-Regulation

To elucidate if microglial P2Y12 receptor (P2Y12R) mechanisms are involved in the trigeminal spinal subnucleus caudalis (Vc; also known as the medullary dorsal horn) in intraoral cancer pain, we developed a rat model of tongue cancer pain. Squamous cell carcinoma (SCC) cells were inoculated into the tongue of rats; sham control rats received the vehicle instead. Nociceptive behavior was measured as the head-withdrawal reflex threshold (HWRT) to mechanical or heat stimulation applied to the tongue under light anesthesia. On day 14 after the SCC inoculation, activated microglia and P2Y12R expression were examined immunohistochemically in the Vc. The HWRT was also studied in SCC-inoculated rats with successive intra-cisterna magna (i.c.m.) administration of specific P2Y12R antagonist (MRS2395) or intraperitoneal administration of minocycline, a microglial activation inhibitor. Tongue cancer was histologically verified in SCC-inoculated rats, within which the HWRT to mechanical stimulation of the tongue was significantly decreased, as compared with that of vehicle-inoculated rats, although the HWRT to heat stimulation was not. Microglia was strongly activated on day 14, and the administration of MRS2395 or minocycline reversed associated nocifensive behavior and microglial activation in SCC-inoculated rats for 14 d. The activity of Vc wide dynamic range nociceptive neurons was also recorded electrophysiologically in SCC-inoculated and sham rats. Background activity and noxious mechanically evoked responses of wide dynamic range neurons were significantly increased in SCC-inoculated rats versus sham rats, and background activity and mechanically evoked responses were significantly suppressed following i.c.m. administration of MRS2395 in SCC-inoculated rats as compared with sham. The present findings suggest that SCC inoculation that produces tongue cancer results in strong activation of microglia via P2Y12 signaling in the Vc, in association with increased excitability of Vc nociceptive neurons, reflecting central sensitization and resulting in tongue mechanical allodynia.

Topics: Adenine; Animals; Cancer Pain; Carcinoma, Squamous Cell; Immunohistochemistry; Male; Microglia; Minocycline; Neuralgia; Nociceptors; Rats; Rats, Inbred F344; Receptors, Purinergic P2Y12; Signal Transduction; Tongue Neoplasms; Trigeminal Nucleus, Spinal; Valerates

To investigate the mechanisms underlying the anti-nociceptive effect of minocycline on bone cancer pain (BCP) in rats.. A rat model of BCP was established by inoculating Walker 256 mammary carcinoma cells into tibial medullary canal. Two weeks later, the rats were injected with minocycline (50, 100 μg, intrathecally; or 40, 80 mg/kg, ip) twice daily for 3 consecutive days. Mechanical paw withdrawal threshold (PWT) was used to assess pain behavior. After the rats were euthanized, spinal cords were harvested for immunoblotting analyses. The effects of minocycline on NF-κB activation were also examined in primary rat astrocytes stimulated with IL-1β in vitro.. BCP rats had marked bone destruction, and showed mechanical tactile allodynia on d 7 and d 14 after the operation. Intrathecal injection of minocycline (100 μg) or intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced mechanical tactile allodynia. Furthermore, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of GFAP (astrocyte marker) and PSD95 in spinal cord. Moreover, intraperitoneal injection of minocycline (80 mg/kg) reversed BCP-induced upregulation of NF-κB, p-IKKα and IκBα in spinal cord. In IL-1β-stimulated primary rat astrocytes, pretreatment with minocycline (75, 100 μmol/L) significantly inhibited the translocation of NF-κB to nucleus.. Minocycline effectively alleviates BCP by inhibiting the NF-κB signaling pathway in spinal astrocytes.

Topics: Analgesics; Animals; Anti-Bacterial Agents; Astrocytes; Bone Neoplasms; Cancer Pain; Cell Line, Tumor; Female; Hyperalgesia; Minocycline; NF-kappa B; Rats, Wistar; Signal Transduction; Spinal Cord