Biology subjects

Uddin, O.

Publications and source records attributed to Uddin, O..

4 recordsLinked to original sources

bioRxiv2020

Divergent profiles of fentanyl withdrawal and associated pain in mice and rats

Opioid abuse has devastating effects on patients, their families, and society. Withdrawal symptoms are severely unpleasant, prolonged, and frequently hinder recovery or lead to relapse. The sharp increase in abuse and overdoses arising from the illicit use of potent and rapidly-acting synthetic opioids, such as fentanyl, highlights the urgency of understanding the withdrawal mechanisms related to these drugs. Progress is impeded by inconsistent reports on opioid withdrawal in different preclinical models. Here, using rats and mice of both sexes, we quantified withdrawal behaviors during spontaneous and naloxone-precipitated withdrawal, following two weeks of intermittent fentanyl exposure. We found that both mice and rats lost weight during exposure and showed increased signs of distress during spontaneous and naloxone precipitated withdrawal. However, these species differed in their expression of withdrawal associated pain, a key contributor to relapse in humans. Spontaneous or ongoing pain was preferentially expressed in rats in both withdrawal conditions, while no change was observed in mice. In contrast, withdrawal associated thermal hyperalgesia was found only in mice. These data suggest that rats and mice diverge in how they experience withdrawal and which aspects of the human condition they most accurately model. These differences highlight each species strengths as model systems and can inform experimental design in studies of opioid withdrawal.

neuroscience↗

bioRxiv2020

Parabrachial complex processes dura inputs through a direct trigeminal ganglion-to-parabrachial connection

Migraines cause significant disability and contribute heavily to healthcare costs. Irritation of the meninges outermost layer (the dura mater), and trigeminal ganglion activation contribute to migraine initiation. Maladaptive changes in central pain-processing regions are also important in maintaining pain. The parabrachial complex (PB) is a central region that mediates chronic pain. PB receives diverse sensory information, including a direct input from the trigeminal ganglion. We hypothesized that PB processes inputs from the dura. Using in vivo electrophysiology recordings from single units in anesthetized rats we identified 58 neurons in lateral PB that respond reliably and with short latency to electrical dura stimulation. After injecting tracer into PB, anatomical examination reveals retrogradely labeled cell bodies in the trigeminal ganglion. Neuroanatomical tract-tracing revealed a population of neurons in the trigeminal ganglion that innervate the dura and project directly to PB. These findings indicate that PB is strategically placed to process dura inputs, and suggest that it is directly involved in the pathogenesis of migraine headaches.

neuroscience↗

bioRxiv2020

Ventral arkypallidal neurons modulate accumbal firing to promote reward consumption.

A pause in firing of nucleus accumbens shell (NAcSh) neurons is critical for reward consumption; however, the substrate driving this pause is unknown. While ventral pallidal (VP) activity encodes reward value, the specific roles of VP subpopulations in computation and expression of this value are poorly understood. Here, we establish that inhibitory input from the VP is crucial for reward-related inhibition of NAc firing. A sparse, non-canonical subpopulation of VP neurons, the so-called "ventral arkypallidal (vArky)" neurons makes inhibitory synaptic contacts throughout the NAcSh, and drives inhibition of NAcSh neurons in vivo. Moreover, endogenous calcium activity of vArky neurons predicted subsequent reward consumption behavior, while optogenetically activating this pathway increased reward consumption by amplifying hedonic value of reward. Classically, the VP is considered downstream of the NAc; however, our results challenge this view and establish that vArky neurons in the VP promote reward consumption via potent modulation of NAcSh firing.

neuroscience↗

bioRxiv2020

An amygdalo-parabrachial pathway regulates pain perception and chronic pain

The parabrachial (PB) complex mediates both ascending nociceptive signaling and descending pain modulatory information in the affective/emotional pain pathway. We have recently reported that chronic pain is associated with amplified activity of PB neurons in a rat model of neuropathic pain. Here we demonstrate that similar activity amplification occurs in mice, and that this is related to suppressed inhibition to PB neurons from the central nucleus of the amygdala (CeA). Animals with pain after chronic constriction injury of the infraorbital nerve (CCI-Pain) displayed higher spontaneous and evoked activity in PB neurons, and a dramatic increase in after-discharges--responses that far outlast the stimulus--compared to controls. PB neurons in CCI-Pain animals showed a reduction in inhibitory, GABAergic inputs. We show that--in both rats and mice--PB contains few GABAergic neurons, and that most of its GABAergic inputs arise from CeA. These CeA GABA neurons express dynorphin, somatostatin and/or corticotropin releasing hormone. We find that the efficacy of this CeA-LPB pathway is suppressed in chronic pain. Further, optogenetically stimulating this pathway suppresses acute pain, and inhibiting it, in naive animals, evokes pain behaviors. These findings demonstrate that the CeA-LPB pathway is critically involved in pain regulation, and in the pathogenesis of chronic pain. Significance StatementWe describe a novel pathway, consisting of inhibition by dynorphin, somatostatin and corticotropin-releasing hormone expressing neurons in the central nucleus of the amygdala that project to the parabrachial nucleus (PB). We show that this pathway regulates the activity of pain-related neurons in PB, and that, in chronic pain, this inhibitory pathway is suppressed, and that this suppression is causally related to pain perception. We propose that this amygdalo-parabrachial pathway is a key regulator of both chronic and acute pain, and a novel target for pain relief.

neuroscience↗