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
