Administrations of thalidomide into the rostral ventromedial medulla produce antinociceptive effects in a rat model of postoperative pain
The descending nociceptive system involves multiple nuclei. Studies have demonstrated that the rostral ventromedial medulla (RVM) is critically involved in pain signal transmissions by sending projections to the spinal cord and trigeminal brain stem nuclei (Drummond & Knudsen, 2011; Millan, 2002; Ossipov, Dussor, & Porreca, 2010; Ren & Dubner, 2002). Additionally, activation of descending nociceptive system results in hyperalgesia and allodynia in various animal pain models (Dubner & Ren, 2004; Gebhart, 2004; Porreca, Ossipov, & Gebhart, 2002; Vanegas & Schaible, 2004), and descending facilitation from the RVM has been demonstrated in a rat model of postoperative pain (Rivat et al., 2009).
Importantly, recent research has shown that thalidomide treatment can reduce thermal hyperalgesia and allodynia in an animal model of neuropathic pain (Cata, Weng, & Dougherty, 2008), and strongly attenuate the mechanical allodynia in an animal model of type 1 diabetic neuropathy (Chauhan, Taliyan, & Sharma, 2012; Huang et al., 2014; Taliyan & Sharma, 2012). These effects likely involve the RVM, since intra‐RVM thalidomide treatment was able to dose‐dependently decrease mechanical allodynia in diabetic rats (Yang et al., 2016). Importantly, many studies have demonstrated that antinociceptive effects of thalidomide are due to reducing the synthesis of TNFα and other pro‐inflammatory cytokines including IL‐1β (Sampaio, Sarno, Galilly, Cohn, & Kaplan, 1991; Singhal & Mehta, 2002). In fact, pro‐inflammatory cytokines, such IL‐1β has been shown to inhibit the function of cannabinoid receptor subtype 1 (CB1) in the striatum (Gentile et al., 2016; Rossi et al., 2012). Furthermore, activation of cannabinoid receptor can produce antinociception after either systemic or central administration (Howlett, 1995; Smith, Cichewicz, Martin, & Welch, 1998). Microinjections of cannabinoid agonists into the RVM can induce antinociception (Martin, Tsou, & Walker, 1998) and the antinociceptive effects of systemic cannabinoids treatment depend on the functional integrity of the RVM (Meng, Manning, Martin, & Fields, 1998), and more specifically on the suppression of GABAergic neurotransmission in the RVM (Lau & Vaughan, 2014). These results suggested that intra‐RVM administrations of thalidomide might have antinociceptive effects by activation of cannabinoid receptors. However, the effects of thalidomide on cannabinoid receptor expression in the RVM remain unclear.
Therefore, in the present study, we evaluated the neurobiological mechanisms of thalidomide within the RVM in the regulation of postoperative pain. To this end, we used a rat model of postoperative pain to examine the effects of intra‐RVM thalidomide treatments on postoperative pain. Then, the effects of intra‐RVM thalidomide treatment on GABAergic neurotransmission in the RVM neurons were also investigated. We further assessed the role of cannabinoid receptor in the effects of intra‐RVM thalidomide treatment on GABAergic neurotransmission in the RVM neurons, and evaluated the effects of thalidomide treatment on the expression levels of cannabinoid receptor subtypes (i.e., CB1 and CB2).