Affective Analgesia Following Muscarinic Activation of the Ventral Tegmental Area in Rats

Abstract

Cholinergic stimulation of dopamine neurons in the ventral tegmental area (VTA) underlies activation of the brain reward circuitry. Activation of this circuit is proposed to preferentially suppress the affective reaction to noxious stimulation. Vocalization afterdischarges (VADs) are a validated model of the affective response of rats to noxious tailshock. The antinociceptive action of the acetylcholine agonist carbachol microinjected into the VTA on VAD threshold was compared to its effect on the thresholds of other tailshock-elicited responses (VDS = vocalizations during shock, and SMR = spinal motor reflexes). Whereas VADs are organized within the forebrain, VDSs and SMRs are organized at medullary and spinal levels of the neuraxis, respectively. Carbachol (1 μg, 2 μg, and 4 μg) injected into VTA produced dose-dependent increases in VAD and VDS thresholds, although increases in VAD threshold were significantly greater than increases in VDS threshold. Administration of carbachol into VTA failed to elevate SMR threshold. Elevations in vocalization thresholds produced by intra-VTA carbachol were reversed in a dose-dependent manner by local administration of the muscarinic receptor antagonist atropine sulfate (30 μg and 60 μg). These results provide the first demonstration of the involvement of the VTA in muscarinic-induced suppression of pain affect.Perspective-Cholinergic activation of the brain reward circuit produced a preferential suppression of rats' affective reaction to noxious stimulation. The neurobiology that relates reinforcement to suppression of pain affect may provide insights into new treatments for pain and its associated affective disorders.

Separating analgesia from reward within the ventral tegmental area

“…Consistent with our previous reports (Borszcz, 1993; Harte et al, 2000; Nandigama and Borszcz, 2003; Kender et al, 2008), responses organized rostrally within the neuraxis were rarely generated without those integrated more caudally. VAD generation, without concomitant elicitation of VDS and SMR occurred on 1.14% of all trials.…”

“…Consistent with the affective analgesia hypothesis, we reported that microinjection of carbachol into VTA produced dose-dependent suppression of vocalization discharges (VADs) in rats (Kender et al, 2008). VADs occur immediately following application of noxious tail shock and are a validated rodent model of pain affect (Caroll and Lim, 1960; Borszcz, 1993, 1995, 2006; Borszcz and Spuz, 2009).…”

“…Every animal in the nicotinic antagonism group received unilateral injections of saline + saline, saline + 4 μg carbachol, 15 μg mecamylamine + 4 μg carbachol, 45 μg mecamylamine + 4μg carbachol, and saline + 45 μg mecamylamine. Doses of drugs were taken from our earlier report (Kender et al, 2008) and from results of preliminary experiments. All drugs were dissolved in normal sterile saline solution.…”

NMDA or Non-NMDA Receptor Antagonism Within the Amygdaloid Central Nucleus Suppresses the Affective Dimension of Pain in Rats: Evidence for Hemispheric Synergy

“…26–29,35,44 The failure to observe an increase in SMR threshold does not reflect the resistance of this response to antinociceptive treatments. In previous studies, administration of morphine into the rostral ventromedial medulla or ventrolateral periaqueductal gray (vlPAG) produced significant increases in SMR, VDS, and VAD thresholds 8,9,11,14 and the intrathecal administration of morphine, serotonin, or norepinephrine was equally effective in raising SMR, VDS, and VAD thresholds.…”

Reward and motivation in pain and pain relief

“…Assessment of analogous affective aspects of pain in nonverbal animals has been challenging. Several preclinical approaches have been employed for this purpose, including vocalization after discharge in rats following electrical tail shock 60 and evaluation of facial grimace that detects pain affect of short and intermediate, but not longer, duration 61 . Recently, operant measures have been developed that use pain-motivated behavior to capture affective features of pain in animals.…”