Protein Kinase A–Dependence of the Supraspinally Mediated Analgesic Effects of Gabapentin on Thermal and Mechanical Hypersensitivity

Abstract

Abstract. We have recently shown that gabapentin generates protein kinase A (PKA)-dependent presynaptic inhibition of GABAergic synaptic transmission in locus coeruleus (LC) neurons only under neuropathic states. To verify behaviorally this in vitro electrophysiological finding, the PKA inhibitor H-89 was injected intracerebroventricularly (i.c.v.) before supraspinal application of gabapentin in mice developing thermal and mechanical hypersensitivity after peripheral nerve injury. H-89 dose-dependently attenuated the analgesic effects of i.c.v.-injected gabapentin, suggesting that PKA-dependent removal of GABAergic inhibition of LC neurons is the most plausible synaptic mechanism underlying the supraspinally mediated analgesic effects of gabapentin involving activation of the descending noradrenergic pain-inhibitory system. Keywords: neuropathic pain, gabapentin, protein kinase A (PKA)The anti-hypersensitivity actions of gabapentin have been well established, although we are still on the way to full understanding of its underlying mechanisms. We have been focusing on the supraspinal structure as a possible site for its action and have demonstrated that intracerebroventricular (i.c.v.) administration of gabapentin indeed decreases thermal and mechanical hypersensitivity by activating the descending noradrenergic system in a murine chronic pain model involving partial ligation of the sciatic nerve (1 -3). Our conclusions are supported by Hayashida et al. (4) who have observed recruitment of the descending noradrenergic system by gabapentin in both animal and human postoperative pain conditions. Our recent electrophysiological experiments have shown that gabapentin presynaptically reduces GABAergic inhibitory postsynaptic currents (IPSCs) in locus coeruleus (LC) neurons in slices taken from mice only after peripheral nerve injury (5), thereby removing inhibitory influences on LC neurons, leading to activation of the descending noradrenergic system to relieve neuropathic pain. Recent lines of evidence indicate that several protein kinases including PKC and PKA play crucial roles in mediating not only the pathophysiology of chronic pain after nerve injury or inflammation, but also the hyperalgesia-dependent pharmacological actions of gabapentin (6, 7). Interestingly, our in vitro electrophysiological study demonstrated that the PKA inhibitor H-89, but not the PKC inhibitor chelerythrine, abolished the inhibitory action of subsequently superfused gabapentin on IPSCs in LC neurons in slices taken from mice after peripheral nerve injury, suggesting that PKA activity plays an important role in supraspinal gabapentin responsiveness in neuropathic conditions. The aim of the present study was to behaviorally verify this in vitro electrophysiological finding (5).All of the experimental protocols were approved by the Animal Care and Use Committee of Nagoya City University, and were carried out according to the guidelines of the National Institutes of Health and The Japanese Pharmacological Society.We employed a murine neurop...

Retracted: Comparison of Central versus Peripheral Delivery of Pregabalin in Neuropathic Pain States

“…There is overlap between the tissues that receive pregabalin from intranasal and intrathecal delivery-it is probable that both forms of delivery impacted upon the dorsal horn region, but there may have been some undefined impact of intranasal pregabalin delivery at supraspinal locations as well (even with the lack of impact upon CaVα 2 δ-1 expression in brain). The absence of heightened CaVα 2 δ-1 expression at the supraspinal locations does not exclude the possibility of pregabalin possessing a role in supraspinal pain processing-it is possible that pregabalin may have important effects at the medulla and cortex [65–68]; this may explain the effects of intranasal pregabalin delivery, which only resulted in small concentrations of pregabalin in the lumbar spinal cord and dorsal root ganglia. Pregabalin's effects within the cerebrum may be contributory, especially after demonstrations of high cerebral concentratons of pregabalin following its intranasal delivery.…”

Chronic pregabalin inhibits synaptic transmission between rat dorsal root ganglion and dorsal horn neurons in culture

“…Previous work has identified actions at the cellular level for PGB and GBP, as well as widespread behavioral effects 1 , 7 , 12 , 16 . However, the mechanism of action of gabapentinoid drugs on the sensory networks involved in peripheral nociception, including those of the afferent DRG fibers and the initial processing in the DH, remains poorly defined.…”