Nonopioid actions of intrathecal dynorphin evoke spinal excitatory amino acid and prostaglandin E2 release mediated by cyclooxygenase-1 and -2 - PubMed (original) (raw)

Nonopioid actions of intrathecal dynorphin evoke spinal excitatory amino acid and prostaglandin E2 release mediated by cyclooxygenase-1 and -2

Lee Koetzner et al. J Neurosci. 2004.

Abstract

Spinal dynorphin is hypothesized to contribute to the hyperalgesia that follows tissue and nerve injury or sustained morphine exposure. We considered that these dynorphin actions are mediated by a cascade involving the spinal release of excitatory amino acids and prostaglandins. Unanesthetized rats with lumbar intrathecal injection and loop dialysis probes received intrathecal NMDA, dynorphin A(1-17), or dynorphin A(2-17). These agents elicited an acute release of glutamate, aspartate, and taurine but not serine. The dynorphin peptides and NMDA also elicited a long-lasting spinal release of prostaglandin E2. Prostaglandin release evoked by dynorphin A(2-17) or NMDA was blocked by the NMDA antagonist amino-5-phosphonovalerate as well the cyclooxygenase (COX) inhibitor ibuprofen. To identify the COX isozyme contributing to this release, SC 58236, a COX-2 inhibitor, was given and found to reduce prostaglandin E2 release evoked by either agent. Unexpectedly, the COX-1 inhibitor SC 58560 also reduced dynorphin A(2-17)-induced, but not NMDA-induced, release of prostaglandin E2. These findings reveal a novel mechanism by which elevated levels of spinal dynorphin seen in pathological conditions may produce hyperalgesia through the release of excitatory amino acids and in part by the activation of a constitutive spinal COX-1 and -2 cascade.

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Figures

Figure 1.

Evoked release of glutamate. The concentration of glutamate in dialysate was determined from samples collected at 10 min intervals for a total of 40 min. Baseline levels and glutamate levels at 10 min intervals after the intrathecal injection of artificial CSF (A), NMDA (4 nmol; B), dynorphin A(1-17) (30 nmol; C), or dynorphin A(2-17) (30 nmol; D) were measured. Data are expressed as percentages of the fractions collected before injection. Release after NMDA or des-tyrosyl dynorphin (but not native dynorphin) is different from artificial CSF (all p < 0.05).

Figure 2.

Evoked release of PGE2. The concentration of PGE2 in dialysate was determined from samples collected at 20 min intervals for a total of 60 min. Baseline levels of PGE2 and PGE2 levels at 20 min intervals after the intrathecal injection of artificial CSF (A), NMDA (4 nmol; B), dynorphin A(1-17) (30 nmol; C), or dynorphin A(2-17) (30 nmol; D) were measured. Data are expressed as percentages of the fractions collected before injection. Release after NMDA (but not dynorphin treatment) is not significantly different from that seen after injection of artificial CSF (all p > 0.05).

Figure 3.

NMDA-evoked release of PGE2. Dialysate PGE2 concentrations were monitored before and after intrathecal injection of NMDA (4 nmol). Samples were collected before injection and at 20 min intervals after the intrathecal injection of NMDA. The rats were pretreated with AP-5 (30 μg, intrathecal) 10 min before NMDA (A), ibuprofen (30 mg/kg, i.p.) 50 min before NMDA (B), the COX-1 inhibitor SC 58560 (30 mg/kg, i.p.) 30 min before NMDA (C), or the COX-2 inhibitor SC 58236 (30 mg/kg, i.p.) 30 min before NMDA (D). The pretreatment with AP-5, ibuprofen, or the COX-2 inhibitor SC 58236 significantly (p ≤ 0.05) reduced NMDA-evoked release of PGE2. In contrast, the pretreatment with the COX-1 inhibitor SC 58560 did not reduce NMDA-evoked release of PGE2.

Figure 4.

Dynorphin A(2-17)-evoked release of PGE2. The dialysate PGE2 concentrations were monitored before and after intrathecal injection of dynorphin A(2-17) (30 nmol). Samples were collected before injection and at 20 min intervals after the intrathecal injection of dynorphin. The rats were pretreated with AP-5 (30 μg, intrathecal) 10 min before dynorphin (A), ibuprofen (30 mg/kg, i.p.) 50 min before dynorphin (B), the COX-1 inhibitor SC 58560 (30 mg/kg, i.p.) 30 min before dynorphin (C), or the COX-2 inhibitor SC 58236 (30 mg/kg, i.p.) 30 min before dynorphin (D). The pretreatment with AP-5, ibuprofen, the COX-1 inhibitor SC 58560, or the COX-2 inhibitor SC 58236 all significantly (*p ≤ 0.05) reduced dynorphin A(2-17)-evoked release of PGE2.

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Nonopioid actions of intrathecal dynorphin evoke spinal excitatory amino acid and prostaglandin E2 release mediated by cyclooxygenase-1 and -2 - PubMed (original) (raw)