Separating analgesia from reward within the ventral tegmental area
Introduction
The addictive liability of analgesics has persistently vexed the treatment of pain. More than a century ago, it was observed that strong analgesics, like opiates and psychostimulants, are highly abused and self-administered by both humans and animals (Spender, 1887, UKMH, 1926, Himmelsbach, 1942, May, 1953). Currently, the nonmedical use of prescription pain relievers is greater than the combined abuse of cocaine, hallucinogens, inhalants, and heroin (SAMHSA, 2011). Moreover, the number of overdose deaths from prescription pain relievers far outnumbered deaths from heroin and cocaine combined in the past decade (NIDA, 2011). Thus, identifying neural mechanisms by which strong analgesics alleviate pain while limiting the potential for addiction is a societal imperative.
The link between analgesia and addiction suggests that the neural substrates of antinociception and reward overlap (Oberst et al., 1943). Franklin, 1989, Franklin, 1998 proposed that the ability of opiates and psychostimulants to induce positive affect underlies their addictive liability and analgesic action. The positive affective state generated by these analgesics presumably reduces the distress that normally accompanies noxious stimulation and injury. This phenomenon is termed “affective analgesia” and reflects preferential suppression of the emotional response to pain.
Activation of dopamine neurons in the ventral tegmental area (VTA) that project to nucleus accumbens (NAc) contributes to reward produced by morphine, amphetamine, other drugs of abuse, and natural reinforcers (Schultz, 2000, Di Chiara, 2002, Kiyatkin, 2002, Wise, 2004, Koob and Volkow, 2010). Activation of this mesoaccumbal dopamine system also contributes to the antinociceptive action of morphine and amphetamine (Altier and Stewart, 1998). These neurons are endogenously activated via cholinergic projections from the laterodorsal tegmental (LTDg) and pedunculopontine tegmental (PPTg) nuclei (Blaha et al., 1996, Omelchenko and Sesack, 2005, Omelchenko and Sesack, 2006) acting on muscarinic and nicotinic receptors (Nisell et al., 1994, Yeomans and Baptista, 1997, Gronier and Rasmussen, 1998, Miller et al., 2005). Microinjecting nicotinic and muscarinic agonists into the VTA excite dopaminergic neurons via activation of local cholinergic receptors (Calabresi et al., 1989, Lacey et al., 1990) and increase the efflux of dopamine in NAc (Gronier et al., 2000, Nisell et al., 1994). Cholinergic activation of mesoaccumbal dopamine neurons contributes to reward (Rada et al., 2000). For example, intra-VTA administration of the nonspecific cholinergic agonist carbachol supports the development of conditioned place preference (CPP) learning, and rats learn to self-administer carbachol into VTA, effects mediated by the local muscarinic and nicotinic receptors (Yeomans et al., 1985, Ikemoto and Wise, 2002). Additionally, the capacity of systemically administered morphine to support CPP learning and induce the efflux of dopamine into NAc is partially dependent on acetylcholine receptors in VTA (Miller et al., 2005, Rezayof et al., 2007).
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 the application of noxious tail shock and are a validated rodent model of pain affect (Carroll and Lim, 1960, Borszcz, 1993, Borszcz, 1995, Borszcz, 2006, Borszcz and Spuz, 2009). However, regional differences within VTA were reported in the capacity of carbachol to activate the brain reward circuit. Carbachol supports the development of CPP and is self-administered when delivered to posterior VTA (pVTA), but not the anterior VTA (aVTA) (Ikemoto and Wise, 2002). In our earlier study, affective analgesia followed the administration of carbachol into pVTA, but its suppression of VADs when microinjected into aVTA was not assessed. Here we further evaluated the affective analgesia hypothesis by examining regional differences within VTA in the ability of carbachol to support affective analgesia and reward. We also analyzed the contribution of muscarinic and nicotinic receptors to the effects of carbachol within each VTA subregion. Our goal was to determine whether affective analgesia and reward can be neuropharmacologically separated within the VTA.
Section snippets
Animals
One hundred and thirty-six naïve male Long–Evans rats were housed as pairs in polypropylene cages (52 cm × 28 cm × 22 cm) with hardwood chip bedding and given ad libitum access to Rodent Lab Diet 5001 (PMI, Nutrition International, Inc., Brentwood, MO) and water. Housing was provided in a climate-controlled vivarium maintained on a 12:12-h circadian cycle with lights on at 0700 h. All testing was conducted between 0800 and 1700 h. Upon arrival, rats were given 5–7 days of acclimatization prior to
TH immunohistochemistry
Fig. 1 shows the distribution of catecholaminergic neurons within aVTA (top), midVTA (middle) and pVTA (bottom) of the adult male Long–Evans rat. The aVTA and pVTA were defined as located within the ventral midbrain dorsal to the mammillary bodies (4.68–5.16 mm posterior to bregma) and dorsal to the interpeduncular nucleus (5.88–6.60 mm posterior to bregma), respectively. These coordinates are similar to those previously reported for aVTA and pVTA (Ikemoto and Wise, 2002). The midVTA had not been
Discussion
This study is the first to directly compare the extent of overlap between cholinergically mediated reward and affective analgesia within different regions of VTA. Development of CPP learning and increases in VAD threshold were used as measures of reward and affective analgesia, respectively. We tested Franklin’s affective analgesia hypothesis that postulates that activation of the brain reward circuit preferentially suppresses the affective dimension of pain (Franklin, 1989, Franklin, 1998).
Conclusion
The affective dimension of pain has a profound impact on human health. It motivates those in pain to seek health care, and underlies the development of emotional disturbances such as anxiety, fear, and depression that contribute to the suffering of patients in chronic pain (Loeser, 2000). The use of strong prescription analgesics that are effective in suppressing the affective dimension of pain has increased dramatically, as has the non-medical use, abuse, and dependence on these analgesics,
Acknowledgments
This work was funded by National Institute of Neurological Disorders and Stroke (grant R01 NS-045720) and a faculty research development grant from Wayne State University. We thank Cole S. Lati, and Joshua M. Lucas for technical assistance. This research was conducted in partial fulfillment of the requirements for a doctorate of philosophy in Psychology from Wayne State University by E.S.
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