Spinal 12-lipoxygenase-derived hepoxilin A₃contributes to inflammatory hyperalgesia via activation of TRPV1 and TRPA1 receptors

Abstract

Peripheral inflammation initiates changes in spinal nociceptive processing leading to hyperalgesia. Previously, we demonstrated that among 102 lipid species detected by LC-MS/MS analysis in rat spinal cord, the most notable increases that occur after intraplantar carrageenan are metabolites of 12-lipoxygenases (12-LOX), particularly hepoxilins (HXA 3 and HXB 3 ). Thus, we examined involvement of spinal LOX enzymes in inflammatory hyperalgesia. In the current work, we found that intrathecal (IT) delivery of the LOX inhibitor nordihydroguaiaretic acid prevented the carrageenan-evoked increase in spinal HXB 3 at doses that attenuated the associated hyperalgesia. Furthermore, IT delivery of inhibitors targeting 12-LOX (CDC, Baicalein), but not 5-LOX (Zileuton) dosedependently attenuated tactile allodynia. Similarly, IT delivery of 12-LOX metabolites of arachidonic acid 12(S)-HpETE, 12(S)-HETE, HXA 3 , or HXB 3 evoked profound, persistent tactile allodynia, but 12(S)-HpETE and HXA 3 produced relatively modest, transient heat hyperalgesia. The pronociceptive effect of HXA 3 correlated with enhanced release of Substance P from primary sensory afferents. Importantly, HXA 3 triggered sustained mobilization of calcium in cells stably overexpressing TRPV1 or TRPA1 receptors and in acutely dissociated rodent sensory neurons. Constitutive deletion or antagonists of TRPV1 (AMG9810) or TRPA1 (HC030031) attenuated this action. Furthermore, pretreatment with antihyperalgesic doses of AMG9810 or HC030031 reduced spinal HXA 3 -evoked allodynia. These data indicate that spinal HXA 3 is increased by peripheral inflammation and promotes initiation of facilitated nociceptive processing through direct activation of TRPV1 and TRPA1 at central terminals.eicosanoid | pain | central sensitization T issue injury and inflammation are associated with hyperalgesia mediated by facilitated spinal nociceptive processing that can be modulated by lipids derived from arachidonic acid (AA) and other polyunsaturated fatty acids (PUFA), including eicosanoids synthesized via three enzymatic pathways: (i) cyclooxygenase (COX)-prostaglandins (PG); (ii) 5-, 12-, and 12/15-lipoxygenases (LOX)-leukotrienes, hydroxyeicosatetraenoic acids (HETEs), hepoxilins (HXA 3 and HXB 3 ), lipoxins, resolvins, and protectins; and (iii) cytochrome P450-epoxyeicosatrienoic acids and HETEs (1). Substantial evidence indicates that peripheral injury or direct activation of spinal dorsal horn receptors [Neurokinin 1 (NK1), AMPA, and NMDA] increases eicosanoid formation and that spinal delivery of COX inhibitors reduces the associated hyperalgesia (2, 3). Recently, we reported that paw carrageenan increases spinal production of both COX and 12-LOX metabolites of AA, including 12(S)-HETE in cerebrospinal fluid (CSF) and hepoxilins in the lumbar spinal cord (4).Several groups point to a peripheral role for 5-and 12-LOX in nociception, as shown by antihyperalgesic actions of LOX inhibitors administered via systemic routes (5-9). It has been suggested that spinal 12-LOX may play a r...

Prolactin regulates TRPV1, TRPA1, and TRPM8 in sensory neurons in a sex-dependent manner: Contribution of prolactin receptor to inflammatory pain

“…First, inflammation could lead to an increase in the levels of PRL in the spinal cord and other regions of the central nervous system involved in the processing of nociceptive information. TRPV1 and TRPA1 play a role in inflammatory mechanical allodynia possibly via presynaptic mechanisms in the dorsal spinal cord (32,57). A direct action of PRL on TRPs at the same site is possible, since activated microglia could release PRL during inflammation where this release could also contribute to the development of inflammatory hyperalgesia (50).…”

Mechanisms of Transient Signaling via Short and Long Prolactin Receptor Isoforms in Female and Male Sensory Neurons

“…heat and cold) hyperalgesia (2)(3)(4). TRP channels are also involved in hypersensitivity to thermal and mechanical stimuli at presynaptic levels in the dorsal horn of the spinal cord and certain brain stem regions (62,63). In this respect, PRLR isoforms may also contribute to the transient presynaptic regulation of TRPs (3).…”

Prolactin receptor in regulation of neuronal excitability and channels

“…[67][68][69][70][71] Strong evidence links these channels to mediating sensory neuronal activities by modulating the neuronal threshold of activation and efficiency of neurotransmission between sensory and spinal cord neurons. [72][73][74][75] A variety of pain conditions such as those associated with surgical procedures, 9,76 migraine, 11,34 burn, 30 rheumatoid arthritis, 26,27 and osteoarthritis 33 trigger an increase in serum PRL levels in men, and even more so in women. Recent evidence also suggests that inflammation, tissue injury and trauma lead to a sex-dependent up-regulation in extra-pituitary PRL in the vicinity of peripheral and central terminals of sensory neurons.…”