The ventral tegmental area (VTA) is the origin of mesolimbic projections that control the brain reward circuitry. Activation of mesolimbic reward circuitry is postulated to preferentially suppress affective reactions to noxious stimuli (affective analgesia). VTA dopamine neurons are activated via cholinergic inputs, and we observed that microinjections of the acetylcholine agonist carbachol suppressed vocalizations of rats that occur following administration of brief (1 sec) tail shocks (vocalization afterdischarges = VAD). VADs are a validated rodent model of pain affect. Ikemoto & Wise (2002) reported regional differences within the VTA in the capacity of carbachol to support reinforcement. Carbachol was self-administered in the posterior VTA (pVTA), but not anterior VTA (aVTA). The present study evaluated regional (anterior vs. posterior) differences in the VTA in the capacity of carbachol to suppress rats' affective response to pain. As carbachol is a non-specific cholinergic agonist, the present study also evaluated the muscarinic versus nicotinic involvement in intra-VTA carbachol-induced analgesia by administering atropine (muscarinic antagonist) and mecamylamine (nicotinic antagonist) into each VTA region prior to carbachol treatment. Pain behaviors organized at spinal (spinal motor reflexes = SMR), medullary (vocalizations during shock = VDS), and forebrain (VAD) levels of the neuraxis were elicited by tail shock. The threshold current intensity to elicit each behavior was determined following unilateral microinjections of carbachol (1μg or 4μg in 0.25μl), or vehicle, of each antagonist (30 μg/0.25 μl and 60 μg/0.25μl for atropine; 15 μg/0.25 μl and 45 μg/0.25 μl for mecamylamine) and carbachol (4 μg/0.25 μl), or vehicle into the pVTA and the aVTA. In both VTA regions, carbachol preferentially increased the VAD thresholds. Also, this carbachol induced analgesia is mediated more by muscarinic receptors within the pVTA and by both muscarinic and nicotinic receptors within the aVTA, suggesting differential activation of the mesolimbic and mesocortical systems.
Grant R01 NS045720 from the National Institute of Neurological Disorders and Stroke supported this research.
