Role of nucleus accumbens in neuropathic pain: Linked multi-scale evidence in the rat transitioning to neuropathic pain

Abstract

Despite recent evidence implicating the nucleus accumbens (NAc) as causally involved in the transition to chronic pain in humans, underlying mechanisms of this involvement remain entirely unknown. Here we elucidate mechanisms of NAc reorganizational properties (longitudinally and cross-sectionally), in an animal model of neuropathic pain (spared nerve injury, SNI). We observed inter-related changes: 1) In resting-state fMRI, functional connectivity of the NAc to dorsal striatum and cortex was reduced 28 days (but not 5 days) after SNI; 2) contralateral to SNI injury, gene expression of NAc dopamine 1A, 2, and κ-opioid receptors decreased 28 days after SNI; 3) In SNI (but not sham) covariance of gene expression was upregulated at 5 days and settled to a new state at 28 days; and 4) NAc functional connectivity correlated with dopamine receptor gene expression and with tactile allodynia. Moreover, interruption of NAc activity (via lidocaine infusion) reversibly alleviated neuropathic pain in SNI animals. Together, these results demonstrate macroscopic (fMRI) and molecular reorganization of NAc and indicate that NAc neuronal activity is necessary for full expression of neuropathic pain-like behavior.

Reward responsiveness in patients with chronic pain

“…Previous studies have shown that PCP have abnormal opioid systems (Harris et al, 2007) and in the clinic, these patients frequently show reduced response to opioids (Manchikanti et al, 2011). During chronification of pain, changes in the opioid and dopamine systems are accompanied by changes in neuronal activity and connectivity in an animal models of neuropathic pain (Chang et al, 2014), consistent with cross-sectional and longitudinal studies in humans with chronic pain (Baliki et al, 2012). These changes may be linked to both changes in nucleus accumbens volume and reward processing.…”

Intra-nucleus accumbens administration of the calcium/calmodulin-dependent protein kinase II inhibitor AIP induced antinociception in rats with mononeuropathy

“…Previous studies in our laboratory and other laboratories showed that the nucleus accumbens (NAc) is an important limbic structure of the brain with multiple physiological functions, including pain modulation [1,2,13,16,17]. Morphological observations showed that there is very high density of CaMKII in the NAc [21].…”

Manipulation of Neurotransmitter Levels Has Differential Effects on Formalin-Evoked Nociceptive Behavior in Male and Female Mice

“…Studies indicate that dopamine has a role in pain processing, especially in the transition from acute to chronic pain. 12,34,57,67 Other studies have shown that drugs that alter dopamine levels in the CNS have beneficial effects on pain. 15,27 Because PLZ and N 2 -AcPLZ both act by inhibiting the MAO enzyme, they both increase dopamine levels in the CNS.…”