The Effects of Cobalt Protoporphyrin IX and Tricarbonyldichlororuthenium (II) Dimer Treatments and Its Interaction with Nitric Oxide in the Locus Coeruleus of Mice with Peripheral Inflammation

Abstract

Heme oxygenase 1 (HO-1) and carbon monoxide were shown to normalize oxidative stress and inflammatory reactions induced by neuropathic pain in the central nervous system, but their effects in the locus coeruleus (LC) of animals with peripheral inflammation and their interaction with nitric oxide are unknown. In wild-type (WT) and knockout mice for neuronal (NOS1-KO) or inducible (NOS2-KO) nitric oxide synthases with inflammatory pain induced by complete Freund’s adjuvant (CFA), we assessed: (1) antinociceptive actions of cobalt protoporphyrin IX (CoPP), an HO-1 inducer; (2) effects of CoPP and tricarbonyldichlororuthenium(II) dimer (CORM-2), a carbon monoxide-liberating compound, on the expression of HO-1, NOS1, NOS2, CD11b/c, GFAP, and mitogen-activated protein kinases (MAPK) in the LC. CoPP reduced inflammatory pain in different time-dependent manners in WT and KO mice. Peripheral inflammation activated astroglia in the LC of all genotypes and increased the levels of NOS1 and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK 1/2) in WT mice. CoPP and CORM-2 enhanced HO-1 and inhibited astroglial activation in all genotypes. Both treatments blocked NOS1 overexpression, and CoPP normalized ERK 1/2 activation. This study reveals an interaction between HO-1 and NOS1/NOS2 during peripheral inflammation and shows that CoPP and CORM-2 improved HO-1 expression and modulated the inflammatory and/or plasticity changes caused by peripheral inflammation in the LC.

The role of carbon monoxide, heme oxygenase 1, and the Nrf2 transcription factor in the modulation of chronic pain and their interactions with opioids and cannabinoids

“…CoPP activates the expression of HO-1 in the paws, 14 dorsal root ganglia, 48 and loci coeruleus of animals with peripheral inflammatory pain. 16 In summary, these data reveal that the peripheral and central protective roles played by CORM-2 and CoPP during chronic pain are mainly mediated by HO-1 activation ( Figure 2).…”

“…15,[79][80][81][82] Accordingly, the expression of NOS1 and/or NOS2 is upregulated in the dorsal root ganglia, spinal cords, and loci coeruleus of animals with peripheral inflammation. 16,[83][84][85][86] Moreover, hypersensitivity induced by peripheral inflammation is significantly diminished in NOS1-KO and NOS2-KO animals and is reversed by the administration of selective nitric oxide synthase inhibitors. 79,82,83 Interestingly, the systemic administration of CORM-2 and CoPP normalizes the upregulation of NOS1 induced by peripheral inflammation in the dorsal root ganglia and locus coeruleus.…”

“…In the last years, several studies have evaluated the anti-inflammatory and antinociceptive effects of carbon monoxide as well as those produced by activators of inducible heme oxygenase 1 (HO-1) or the nuclear factor-2 erythroid factor-2 (Nrf2) transcription factor alone or in combination with other analgesic compounds in different preclinical pain models. [11][12][13][14][15][16][17][18][19][20][21][22] In this review, we examine, in chronological order, the results obtained by us and other research groups regarding the effects of HO-1 and carbon monoxide in pain, their mechanisms of action during chronic pain, and their effects on the antinociceptive actions of opioids, cannabinoids, and other analgesics during chronic pain. We also revised the effects of Nrf2 transcription factor activators in pain, their effects in the analgesic actions of opioids and cannabinoids as well as on the emotional disorders accompanying chronic pain.…”

“…[13][14][15]46 Numerous studies have demonstrated that the intraperitoneal, intrathecal, and/or oral administration of CO-RMs such as CORM-2 or CORM-3 or specific HO-1 inducers such as cobalt protoporphyrin IX (CoPP) inhibit acute thermal pain, 47 inflammatory pain provoked by the administration of formalin, 12,46 and visceral pain. 46 These treatments also inhibit inflammatory and monoarthritis pain, 11,14,16,46,48,49 neuropathic pain caused by total or partial sciatic nerve ligation, and pain provoked by spinal nerve injury. 15,17,18,30,46,[50][51][52][53][54] These compounds have also been shown to inhibit neuropathic pain caused by vincristine administration 55,56 or associated with type 1 or type 2 diabetes [57][58][59][60] (Figure 1).…”

Editorial of Special Issue “Protective and Detrimental Role of Heme Oxygenase-1”

“…Data obtained by Sorrenti et al, demonstrated that inducible nitric oxide synthase/gamma-Glutamyl-cysteine ligase (iNOS/GGCL) and dimethylarginine dimethylaminohydrolase (DDAH) dysregulation may play a key role in high glucose mediated oxidative stress, whereas HO-1 inducers such as Caffeic acid phenethyl ester (CAPE) or its more potent derivatives may be useful in diabetes and other stress-induced pathological conditions [13]. The study of Moreno et al reveals an interaction between HO-1 and nitric oxide synthase-1 (NOS1)/ nitric oxide synthase-2 (NOS2) during peripheral inflammation and shows that Cobalt protoporphyrin (CoPP) and CO-releasing molecules-2 (CORM-2) improved HO-1 expression and modulated the inflammatory and/or plasticity changes caused by peripheral inflammation in the locus coeruleus [14].…”