The Effects of Intrathecal and Systemic Gabapentin on Spinal Substance P Release

Abstract

Background Gabapentin binds at the extracellular α2δ1 subunit of voltage sensitive calcium channels. Some voltage sensitive calcium channels regulate substance P release from small primary afferents. We sought to determine in vivo if spinal and/or systemic gabapentin at antihyperalgesic doses will attenuate substance P release. Methods Rats prepared with chronic intrathecal (IT) catheters received IT vehicle or gabapentin 10 min before intraplantar formalin (5%, 50μl) injection. For systemic studies, vehicle or gabapentin was delivered intraperitoneally (IP) 15 min before formalin injection. In separate groups of rats, to assess the effect of IT or IP gabapentin upon formalin-evoked substance P release, animals received similar treatment for assessment of flinching, but underwent transcardial perfusion with 4% paraformaldehyde 10 min after the formalin injection. Substance P release was determined by the incidence of neurokinin 1 receptor (NK1r) internalization in the ipsilateral and contralateral superficial dorsal horn in immunofluorescent stained tissues. Results Unilateral intraplantar formalin evoked biphasic hindpaw flinching. IT gabapentin (100 and 200μg) and IP gabapentin (100 and 200 mg/kg) resulted in a dose-dependent reduction in phase 2, but not phase 1 flinching as compared to vehicle-treated rats. Intraplanatar formalin resulted in NK1r internalization in the ipsilateral, but not contralateral, superficial dorsal horn. IT gabapentin (200, but not 100 μg) and IP gabapentin (200, but not 100 mg/kg) significantly reduced ipsilateral NK1r internalization as compared to vehicle-treated control. Importantly, internalization evoked by IT substance P was not blocked by IT gabapentin. Conclusion Systemic and spinal gabapentin have an acute inhibitory effect on the release of substance P from small primary afferents and a concurrent effect upon the initiation of facilitated pain states.

Conus Venom Peptide Pharmacology

“…L-type calcium channel subtypes are expressed in sensory neurons and dorsal horn of the spinal cord, where they could potentially modulate the development of neuropathic pain (Kim et al, 2001). Intrathecal L-type channel antagonists have mixed effects in pain models (see Yaksh, 2006), possibly because nonselective Ca v 1 inhibitors have little effect on afferent substance P release (Takasusuki and Yaksh, 2011) or the role of Ca v 1 changes in different models of pain. More recently, antisense knockdown and microRNA regulation of the Ca v 1.2 in spinal cord has been shown to reverse the development of mechanical signs of neuropathic pain, hyperexcitability of deep dorsal horn neurons, phosphorylation of cAMP response element-binding protein, and induction of cyclooxygenase-2 mRNA in the spinal cord (Fossat et al, 2010), consistent with Ca v 1.2 expression predominantly in neuronal somata and dendrites and its role in gene regulation and plasticity (Murakami et al, 2004;Zhang et al, 2006a).…”

Polyanalgesic Consensus Conference 2012: Recommendations for the Management of Pain by Intrathecal (Intraspinal) Drug Delivery: Report of an Interdisciplinary Expert Panel

“…Recently published preclinical literature regarding the IT use of nonopioid medications is summarized in Table 10(16,70,71,80,117,121–145).…”

Selective Cathepsin S Inhibition with MIV-247 Attenuates Mechanical Allodynia and Enhances the Antiallodynic Effects of Gabapentin and Pregabalin in a Mouse Model of Neuropathic Pain

“…The effects of gabapentin and pregabalin do not appear to be mediated by GABA receptors, but rather via the inhibition of calcium currents mediated by calcium channels containing the a2d-1 subunit (Fink et al, 2002;Sutton et al, 2002). Blockade of these channels leads to reduced release of pronociceptive neurotransmitters and attenuation of postsynaptic excitability in the spinal dorsal horn (Fehrenbacher et al, 2003;Takasusuki and Yaksh, 2011).…”