Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain

Abstract

Gabapentin is a first-line therapy for neuropathic pain but its mechanisms and sites of action remain uncertain. We investigated gabapentin-induced modulation of neuropathic pain following spinal nerve ligation (SNL) in rats. Intravenous or intrathecal gabapentin reversed evoked mechanical hypersensitivity, produced conditioned place preference (CPP) and dopamine release in the nucleus accumbens (NAc) selectively in SNL rats. Spinal gabapentin also significantly inhibited dorsal horn wide dynamic range (WDR) neuronal responses to a range of evoked stimuli in SNL rats. In contrast, gabapentin microinjected bilaterally into the rostral anterior cingulate cortex (rACC), produced CPP and elicited NAc dopamine release selectively in SNL rats but did not reverse tactile allodynia and had marginal effects on WDR neuronal activity. Moreover, blockade of endogenous opioid signaling in the rACC prevented intravenous gabapentin-induced CPP and NAc dopamine release but failed to block its inhibition of tactile allodynia. Gabapentin therefore can potentially act to produce its pain relieving effects by (a) inhibition of injury-induced spinal neuronal excitability, evoked hypersensitivity and ongoing pain and (b) selective supraspinal modulation of affective qualities of pain, without alteration of reflexive behaviors. Consistent with previous findings of pain relief from non-opioid analgesics, gabapentin requires engagement of rACC endogenous opioid circuits and downstream activation of mesolimbic reward circuits reflected in learned pain motivated behaviors. These findings support the partial separation of sensory and affective dimensions of pain in this experimental model and suggest that modulation of affective-motivational qualities of pain may be the preferential mechanism of gabapentin’s analgesic effects in patients.

Etiology and Pharmacology of Neuropathic Pain

“…This very much complicates the search for effective therapeutic targets. Although gabapentinoids may only bind to one specific target, the a2d-1 subunit of voltage-gated Ca 2+ channels (Gee et al, 1996;Field et al, 2006;Offord and Isom, 2015), this interaction has multiple consequences for synaptic transmission, neuron-selective actions, and network excitability at the spinal level (Biggs et al, 2014;Alles and Smith, 2016;Alles et al, 2017) and within higher brain centers (Suzuki et al, 2005;Eroglu et al, 2009;Suto et al, 2014;Crosby et al, 2015;Patel and Dickenson, 2016a;Bannister et al, 2017b); this multiplicity of effect may explain their therapeutic effectiveness. The appreciation of this concept has led to the evidence-based development of drugs that will affect multiple targets Zamponi et al, 2015).…”

“…Several reviews of the pharmacotherapy of neuropathic pain have appeared in the last few years; some are broadly based (Kremer et al, 2016;Yekkirala et al, 2017), whereas others discuss the use of specific agents such as cannabinoids (Luongo et al, 2017), amitriptyline (Moore et al, 2015), Ca 2+ and/or Na + channel blockers (Waxman and Zamponi, 2014;Zamponi et al, 2015;Patel et al, 2017), and agents that potentiate GABAergic inhibition (Zeilhofer et al, 2012a). Because gabapentinoids were originally developed as anticonvulsant agents (Offord and Isom, 2015), much is still to be learned about the mechanism of their antiallodynic effect (Bannister et al, 2017b). This means that the drugs that are used most frequently are the least well understood.…”

“…Supraspinal processing of nociceptive information may be more akin to the human sensation of pain than tests of mechanical, cold, or thermal allodynia. Human pain may be better modeled and evaluated in animals by using operant models such as conditioned place aversion (King et al, 2009;Zhang et al, 2015c;Bannister et al, 2017b) or evaluation of spontaneously emitted behaviors such as facial grimacing (Langford et al, 2010) or examination of changes in social interaction (Mogil, 2009). …”

“…Supraspinal Actions of Gabapentinoids. In addition to its spinal actions, supraspinal mechanisms clearly contribute to the therapeutic effects of gabapentinoids (Bannister et al, 2017b). This is hardly surprising given the ubiquitous distribution of a2d subunits throughout the nervous system (Dolphin, 2012a(Dolphin, ,b, 2013.…”

Mechanisms Underlying Bone and Joint Pain

“…Much has been learned about how stress can activate these descending pain modulatory pathways to dampen pain or induce analgesia through endogenous opioid and cannabinoid signaling within the brain [101]. Following injury, a time-dependent increase in net descending pain facilitation occurs, wherein descending facilitatory pathways promote enhanced spinal cord activity to noxious and non-noxious stimuli [67, 101] as well as behavioral responses showing enhanced responsiveness to noxious and non-noxious stimuli modeling hyperalgesia and allodynia, respectively [102, 103, 77, 104, 105]. …”